Biaryl urea derivative or salt thereof and preparation process and use for the same

ABSTRACT

The present disclosure discloses a biaryl urea RORγt inhibitor, and specifically relates to a biaryl urea derivative, as represented by formula I, with an RORγt inhibiting activity, and a preparation process thereof, and a pharmaceutical composition comprising the compound. Further disclosed is use of the compound for treating an RORγt-related disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 16/312,436, filed Dec. 21, 2018, which is anational phase application of international patent application No.PCT/CN2017/088956, filed on Jun. 19, 2017, which claims the priority ofChinese Patent Applications No. 201610455177.X, field on Jun. 22, 2016,and the priority of Chinese Patent Applications No. 201610455207.7,field on Jun. 22, 2016. The entire contents of those applications areincorporated herein by reference.

TECHNICAL FIELD

The present disclosure belongs to the technical field of chemicalpharmaceuticals, and generally relates to a novel biaryl urea derivativewith an RORγt inhibiting activity represented by general formula I orsalts thereof and a preparation process thereof, and further relates touse of such a compound for treating an RORγt-related disease.

BACKGROUND

Retinoic acid receptor-related orphan receptors (RORs), also known asNF1R, are members of the ligand-dependent transcription factor nuclearreceptor superfamily. The ROR subfamily mainly includes three members:RORα, RORβ and RORγ. There are two different subtypes of RORγ: RORγ1 andRORγt (also known as RORγ2). RORγ1 is distributed in skeletal muscle,thymus, testis, pancreas, prostate, heart, and liver, etc., while RORγtis only expressed in some immune cells.

Littman et al. first reports that RORγt is required for thedifferentiation of naive CD4⁺T cells into Th17 cells. During thedifferentiation of antigen-stimulated Thp cells into Th17 cells, RORγtis expressed under the inducing effect of cytokines such as IL-6, IL-21and TGF-β. Thp cells isolated from RORγt-deficient mice have obviouslydecreased differentiation into Th17 cell lines. These all indicate thatRORγt is the key regulatory factor to promote the differentiation ofTh17 cells.

Th17 cell is one of helper T cells, and may produce IL-17 and otherpro-inflammatory cytokines. Th17 cells have key functions in many mouseautoimmune disease models, such as animal models of experimentalallergic encephalomyelitis (EAE) and collagen-induced arthritis (CIA).In addition, elevated IL-17 levels can be detected in some humanautoimmune diseases such as rheumatoid arthritis (RA), multiplesclerosis (MS), psoriasis and inflammatory bowel disease (IBD). Theincreased Th17 cells are found in tissues and peripheral blood samplesof patients with autoimmune diseases. Therefore, Th17 cells or IL-17cytokine produced by Th17 cells are closely related to the pathogenesisof inflammation and autoimmune diseases.

In January 2015, Cosentyx (Secukinumab/AIN457), a monoclonal antibodydeveloped by Novartis that is used for treatment of psoriasis byspecifically blocking IL-17, has been approved to launch in the marketsby FDA. This is the first drug that acts on IL-17 in drugs for treatmentof psoriasis. This also highlights the importance of the IL-17 signalingpathway in inflammatory diseases and demonstrates the potential fortreatment of inflammatory diseases by affecting the IL-17 signalingpathway with RORγt inhibitors.

Therefore, RORγt can be used as a new target for the treatment ofautoimmune diseases. It is of great significance to search forsmall-molecule modulators for RORγt and use them in the treatment ofRORγt-mediated inflammation and autoimmune diseases.

SUMMARY OF THE INVENTION

The present disclosure provides a class of novel biaryl urea compoundrepresented by general formula I and pharmaceutically acceptable saltsthereof:

wherein:A is a phenyl or heteroaryl;B is a phenyl or heteroaryl;R₁ is optionally selected from a group consisting of hydrogen, methyl,halogen, cyano, hydroxy, —CF₃, —CHF₂, and —CH₂F;R₁′ is optionally selected from a group consisting of hydrogen, halogen,cyano, hydroxy, C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl, C(O)OR_(a)or cycloalkyl-substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxy or C₁-C₃ alkoxyl-substituted C₁-C₃ alkyl, phenyl,substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl,heterocyclooxyl, heteroaryl, heteroaryloxyl, C₂-C₆ alkenyl,halogen-substituted aromatic ketone group, —C(O)R_(a),—(CH₂)_(n)NR_(a1)R_(a2), —(CH₂)_(n)C(O)OR_(a) and —C(O)NR_(a1)R_(a2);R₂ is optionally selected from a group consisting of hydrogen, halogen,cyano, hydroxyl, C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl,C(O)OR_(a) or cycloalkyl substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, phenyl,substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl,heterocyclooxyl, heteroaryl, heteroaryloxyl, C₂-C₆ alkenyl,halogen-substituted aromatic ketone group, carboxyl or cyano substitutedheteroaryl, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2), —(CH₂)_(n)C(O)OR_(a)and —C(O)NR_(a1)R_(a2);R₃ and R₄ are each independently selected from a group consisting ofhydrogen, C₁-C₃ alkyl, halogen-substituted C₁-C₃ alkyl, C₃-C₆ cycloalkyland C₁-C₃ oxo(azo)heterocycloalkyl;R₅ and R₆ are each independently selected from a group consisting ofhydrogen, halogen, cyano, hydroxyl, C₁-C₃ alkyl, halogen-substitutedC₁-C₃ alkyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, C₁-C₃alkoxyl, halogen-substituted C₁-C₃ alkoxyl, C₃-C₆ cycloalkyl and C₃-C₆oxo(zao)heterocycloalkyl, and R₅ and R₆ may also be bonded to form aC₃-C₆ ring;R₇ is optionally selected from a group consisting of hydrogen, halogen,cyano, hydroxyl, C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl,C(O)OR_(a) or cycloalkyl substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, phenyl,substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl,heterocyclooxyl, heteroaryl, heteroaryloxyl, C₂-C₆ alkenyl,halogen-substituted aromatic ketone group, carboxyl or cyano substitutedheteroaryl, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2), —(CH₂)_(n)C(O)OR_(a)and —C(O)NR_(a1)R_(a2);Y is a covalent bond, —NR_(a)—, —O—, —NR_(a)CR_(a1)R_(a2)—,—OCR_(a1)R_(a2)—, —CR_(a1)R_(a2)— or —C(O)NR_(a)—;R₈ is selected from

R₉ is selected from a group consisting of hydroxyl, C₁-C₆ alkyl,halogen-substituted C₁-C₆ alkyl, hydroxyl or C₁-C₃ alkoxyl substitutedC₁-C₃ alkyl, C₂-C₆ alkenyl, —(CH₂)_(n)NR_(a1)R_(a2) and —NHC(O)CH₃;

Z is O or NR_(a);

R_(a), R_(a1) and R_(a2) are each independently selected from hydrogenor C₁-C₃ alkyl; andm, r, t, n and s are each independently selected from any integer valueof 0 to 2.

Preferably, A is a phenyl.

Preferably, s is 1.

Preferably, the structure of the novel biaryl urea compound provided inthe present disclosure is as shown by general formula II:

wherein:B is phenyl or heteroaryl;R₁ is optionally selected from a group consisting of hydrogen, methyl,halogen, cyano, hydroxyl, —CF₃, —CHF₂, and —CH₂F;R₁′ is optionally selected from a group consisting of hydrogen, halogen,cyano, hydroxyl, C₁-C₆ alkyl, halogen substituted C₁-C₆ alkyl,C(O)OR_(a) or cycloalkyl substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, phenyl,substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl,heterocyclooxyl, heteroaryl, heteroaryloxyl, C₂-C₆ alkenyl, halogensubstituted aromatic ketone group, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2),—(CH₂)_(n)C(O)OR_(a) and —C(O)NR_(a1)R_(a2);R₂ is optionally selected from a group consisting of hydrogen, halogen,cyano, hydroxyl, C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl,C(O)OR_(a) or cycloalkyl substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, phenyl,substituted heteroaryloxyl, C₂-C₆ alkenyl, halogen substituted aromaticketone group, carboxyl or cyano substituted heteroaryl, —C(O)R_(a),—(CH₂)_(n)NR_(a1)R_(a2), —(CH₂)_(n)C(O)OR_(a), and —C(O)NR_(a1)R_(a2);R₃ and R₄ are each independently selected from a group consisting ofhydrogen, C₁-C₃ alkyl, halogen-substituted C₁-C₃ alkyl, C₃-C₆ cycloalkyland C₃-C₆ oxo(azo)heterocycloalkyl;R₅ and R₆ each independently selected from a group consisting ofhydrogen, halogen, cyano, hydroxyl, C₁-C₃ alkyl, halogen-substitutedC₁-C₃ alkyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, C₁-C₃alkoxyl, halogen-substituted C₁-C₃ alkoxyl, C₃-C₆ cycloalkyl and C₃-C₆oxo(azo)heterocycloalkyl, and R₅ and R₆ may also be bonded to form aC₃-C₆ ring;R₇ is optionally selected from a group consisting of hydrogen, halogen,cyano, hydroxyl, C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl,C(O)OR_(a) or cycloalkyl substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl,C₃-C₆ oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, phenyl,substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl,heterocyclooxyl, heteroaryl, heteroaryloxyl, C₂-C₆ alkenyl,halogen-substituted aromatic ketone group, carboxyl or cyano substitutedheteroaryl, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2), —(CH₂)_(n)C(O)OR_(a)and —C(O)NR_(a1)R_(a2);Y is selected from a group consisting of a covalent bond, —NR_(a)—, —O—,—NR_(a)CR_(a1)R_(a2)—, —OCR_(a1)R_(a2)—, —CR_(a1)R_(a2)—, and—C(O)NR_(a)—;

R₈ is

R₉ is selected from a group consisting of hydroxyl, C₁-C₆ alkyl,halogen-substituted C₁-C₆ alkyl, hydroxyl or C₁-C₃ alkoxyl substitutedC₁-C₃ alkyl, C₂-C₆ alkenyl, —(CH₂)_(n)NR_(a1)R_(a2) and —NHC(O)CH₃;

Z is O or NRa;

R_(a), R_(a1) and R_(a2) are each independently selected from hydrogenor C₁-C₃ alkyl; andm, r, t and n are each independently selected from any integer value of0˜2.

Further preferably, B is a phenyl or a six-membered heteroaryl.

Further preferably, R₃ and R₄ are each independently selected fromhydrogen or methyl.

Further preferably, R₁′ is selected from a group consisting of hydrogen,—OCF₃, —OCHF₂, —CF₃ and heteroaryl.

Further preferably, m is 1 and R₁ is selected from a group consisting of—H, —Cl, —F, and —CH₃.

Further preferably, r is 1 or 2 and R₂ is one or two groups selectedfrom —H, —Cl, —F, —CF₃, —OCF₃, —CN, C₁-C₃ alkyl and heteroaryl.

Further preferably, Z is O or NH.

Further preferably, R₇ is optionally selected from hydrogen, halogen,cyano, hydroxyl, and C₁-C₆ alkyl.

Further preferably, R₉ is selected from a group consisting of methyl,ethyl, —NHCH₃, —NH₂ and —NHC(O)CH₃.

Preferably, the structure of the novel biaryl urea compound provided inthe present disclosure is as shown in general formula III:

wherein:

X is CH or N;

R₁ is optionally selected from a group consisting of —H, —Cl, —F, and—CH₃;R₁′ is optionally selected from a group consisting of —H, —OCF₃, —OCHF₂and —CF₃;R₂ is optionally selected from a group consisting of —H, —Cl, —F, —CF₃,—OCF₃, —CN and C₁-C₃ alkyl;R₃ and R₄ are each independently selected from hydrogen or methyl;R₅ and R₆ are each independently selected from a group consisting ofhydrogen, halogen, cyano, hydroxyl, C₁-C₃ alkyl, halogen substitutedC₁-C₃ alkyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, C₁-C₃alkoxyl, halogen substituted C₁-C₃ alkoxyl, C₃-C₆ cycloalkyl and C₃-C₆oxo(azo)heterocycloalkyl, and R₅ and R₆ can be bonded to form a C₃-C₆ring;R₇ is optionally selected from a group consisting of hydrogen, halogen,cyano, hydroxyl, and C₁-C₆ alkyl;Y is a covalent bond, —NR_(a)—, —O—, —NR_(a)CR_(a1)R_(a2)—,—OCR_(a1)R_(a2)—, —CR_(a1)R_(a2)— or —C(O)NR_(a)—;

R₈ is

R₉ is selected from a group consisting of methyl, ethyl, —NHCH₃, —NH₂,and —NHC(O)CH₃;Z is selected from O or NH;R_(a), R_(a1) and R_(a2) are each independently selected from hydrogenor C₁-C₃ alkyl; andr and t are each independently selected from 1 or 2.

Most preferably, the biaryl urea compounds provided in the presentdisclosure include, but are not limited to, the following specificcompounds:

The present disclosure further provides a process for preparing theinventive compounds, comprising the following synthesis schemes.

1. The compound represented by formula 1-1 and the compound representedby formula 1-2 are reacted with Pd₂(dba)₃, potassium phosphate andt-butyltetrafluoroborate under microwave at 110° C. to obtain a compoundrepresented by formula 1-3.

2. The compound represented by formula 1-3 is subjected to a reaction ina solution of SnCl₂ and hydrochloric acid in ethanol at 60° C. to obtaina compound represented by formula 1-4.

3. The compound represented by formula 1-4 is reacted with intermediate1 in the presence of triphosgene and N,N-diisopropylethylamine at atemperature of 0° C. to room temperature to obtain the target compoundrepresented by formula 1-a.

1. The compound represented by formula 2-1 is reacted with an alkylhalide at room temperature to obtain a compound represented by formula2-2 in the presence of NaH or K₂CO₃.

2. The compound represented by formula 2-2 is reacted with intermediate1 in the presence of triphosgene and N,N-diisopropylethylamine at atemperature of 0° C. to room temperature to obtain the target compoundrepresented by formula 2-a.

1. The compound represented by formula 3-1 is reacted with the compoundrepresented by formula 3-2 in the presence of triphosgene andN,N-diisopropylethylamine at a temperature from 0° C. to roomtemperature to obtain a compound represented by formula 3-3.

2. The compound represented by formula 3-3 is first reacted withtrifluoroacetamide, magnesium oxide, rhodium acetate and iodobenzenetetraacetate in dichloromethane at room temperature overnight, and thensubjected to a reaction at room temperature in the presence of potassiumcarbonate/methanol for two hours to obtain the target compoundrepresented by formula 3a.

1. The compound represented by formula 4-1 is reacted with the compoundrepresented by formula 4-2 in the presence of Pd₂(dba)₃, potassiumphosphate or potassium carbonate and t-butyltetrafluoroborate undermicrowave at 110° C. to obtain a compound represented by formula 4-3.

2. The compound represented by formula 4-3 is subjected to a reaction ina solution of SnCl₂/hydrochloric acid in ethanol at 60° C. to obtain acompound represented by formula 4-4.

3. The compound represented by formula 4-4 is reacted with theintermediate A in the presence of triphosgene andN,N-diisopropylethylamine at a temperature of 0° C. to room temperatureto obtain a compound represented by formula 4-5.

4. The compound represented by formula 4-5 is subjected to a reaction atroom temperature in a solution of lithium hydroxide or sodium hydroxidein ethanol/water to obtain the target compound represented by formula4-a.

1. The compound represented by formula 5-1 is reacted with an alkylhalide in the presence of NaH or K₂CO₃ to obtain a compound representedby formula 5-2.

2. The compound represented by formula 5-2 is reacted with theintermediate A in the presence of triphosgene andN,N-diisopropylethylamine at a temperature of 0° C. to room temperatureto obtain a compound represented by formula 5-3.

3. The compound represented by formula 5-3 is subjected to a reaction atroom temperature in a solution of lithium hydroxide or sodium hydroxidein ethanol/water to obtain the target compound represented by formula5-a.

Unless otherwise stated, the groups and terms used in the abovesynthesis schemes have the same meanings as those in the compoundsrepresented by general formulas I, II and III.

The above synthesis schemes are merely illustrative of the preparationmethods for some of the compounds in the present disclosure. For thoseskilled in the art, based on the above synthesis schemes, the inventivecompounds can be synthesized by a similar method according to the commonknowledge in the art.

The “compound”, as used herein, includes all stereoisomers, geometricisomers, tautomers and isotopes.

The “compound”, as used herein, may be asymmetric, for example, havingone or more stereoisomers. Unless otherwise stated, all stereoisomersinclude, for example, enantiomers and diastereomers. The compoundcontaining an asymmetric carbon atom herein can be isolated in anoptically active pure form or in a racemic form. The optically activepure form can be resolved from racemic mixtures or can be synthesizedwith chiral materials or chiral reagents.

The “compound”, as used herein, further includes tautomeric forms. Thetautomeric form is derived from the exchange of a single bond with anadjacent double bond, accompanying with transfer of a proton.

The disclosure also includes atoms of all isotopes, whether in theintermediate or the final compound. The atoms of an isotope includethose having the same number of atoms but different mass numbers.

For example, isotopes of hydrogen include deuterium and tritium.

In the present disclosure, the terms used have the following meaningsunless otherwise specified.

The term “halogen” means fluoro, chloro, bromo or iodo, preferablyfluoro or chloro.

The term “cyano” means —CN.

The term “hydroxyl” means —OH.

The term “carboxy” means —COOH.

The term “alkyl” means a straight or branched saturated hydrocarbongroup consisting of carbon atoms and hydrogen atoms, such as a C₁-C₂₀alkyl group, preferably a C₁-C₆ alkyl, for example, methyl, ethyl,propyl (including n-propyl and isopropyl), butyl (including n-butyl,isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl,isopentyl, neopentyl), n-hexyl, and 2-methylhexyl, etc. The alkyl groupmay be unsubstituted or substituted by one or more substituentsincluding, but not limited to, alkyl, alkoxyl, cyano, hydroxyl,carbonyl, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl,sulfinyl, and phosphoryl.

The term “cycloalkyl” means a monocyclic, fused, spiro or bridged ringwhich solely consists of carbon, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, spiro[3.4]octyl, and bicyclic[3.1.1] hexyl.

The term “heterocycloalkyl” means a monocyclic or fused ring containingone or more heteroatoms of N, O or S, typically, a 5-6 memberedheterocyclyl containing one or more heteroatoms of N, O or S, such aspiperazino, morpholino, piperidino, pyrrolidinyl and derivativesthereof.

The term “aryl” means an all-carbon monocyclic or fused ring having afully conjugated π-electron system, typically having 6 to 14 carbonatoms, preferably having 6 to 12 carbon atoms, and most preferablyhaving 6 carbon atoms. The aryl group may be unsubstituted orsubstituted by one or more substituents including, but not limited to,alkyl, alkoxyl, cyano, hydroxyl, carbonyl, carboxyl, aryl, aralkyl,amino, halogen, sulfonyl, sulfinyl, and phosphoryl. The examples ofunsubstituted aryl groups include, but are not limited to, phenyl,naphthyl, and anthracenyl.

The term “heteroaryl” means a monocyclic or fused ring of 5 to 12 ringatoms, which contains 1 to 4 ring atoms selected from N, O, and S, theremaining ring atoms being C, and has a fully conjugated γ-electronsystem, including but not limited to, pyrrolyl, furyl, thienyl,imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, quinolinyl, isoquinolyl, triazolyl, andtetrahydropyrrolyl. The heteroaryl may be unsubstituted or substituted,the substituents including but not limited to alkyl, alkoxyl, aryl,aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl andheteroalicyclic group.

The term “urea” means a group represented by formula—N(R_(a)R_(b))—C(═O)—NR_(c)R_(d), wherein, R_(a), R_(b), R_(c) and R_(d)are independently selected from hydrogen, alkyl, cycloalkyl,heterocycle, aryl or heteroaryl, etc.

The term “covalent bond” means the interaction formed by share electronpairs.

“Treatment” means any treatment of a disease in a mammal, including: (1)preventing the disease, that is, preventing the progression the symptomof a clinical disease; (2) inhibiting the disease, that is, inhibitingthe development of clinical symptoms; and (3) alleviating the disease,that is, causing remission of clinical symptoms.

The present disclosure further provides a pharmaceutical composition,comprising the compound as described above or a pharmaceuticallyacceptable salt thereof as an active ingredient, and one or morepharmaceutically acceptable carriers.

A “pharmaceutical composition”, as used herein, means a formulation ofone or more compounds of the present disclosure or salt thereof and acarrier generally accepted in the art for delivery of a biologicallyactive compound to an organism (for example, a human). The purpose ofthe pharmaceutical composition is to facilitate delivery of the drug tothe organism.

The term “pharmaceutically acceptable carrier” means a substance whichis co-administered with the active ingredient and facilitates theadministration of the active ingredient, including but not limited toany of acceptable glidants, sweeteners, diluents, preservatives,dyes/colorants, flavor enhancers, surfactants, wetting agents,dispersing agents, disintegrating agents, suspending agents,stabilizers, isotonic agents, solvents or emulsifiers used in human oranimals (for example, livestock) approved by China Food and DrugAdministration, for example, including but not limited to calciumcarbonate, calcium phosphate, sugars and various types of starch,cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

The pharmaceutical composition of the present disclosure can beformulated into solid, semi-solid, liquid or gaseous preparations, suchas tablets, pills, capsules, powders, granules, ointments, emulsions,suspensions, solutions, suppositories, injections, inhalants, gels,microspheres and aerosols, etc.

The pharmaceutical composition of the present disclosure can be producedby a method that is well known in the art, such as a conventional mixingmethod, a dissolution method, a granulation method, a sugar coating pillmethod, a grinding method, an emulsification method, a freeze dryingmethod, etc.

The route of administration of a compound or a pharmaceuticallyacceptable salt thereof or a pharmaceutical composition thereof in thepresent disclosure includes but not limited to oral, rectal,transmucosal, enteral, or topical, transdermal, inhalation, parenteral,sublingual, intravaginal, intranasal, intraocular, intraperitoneal,intramuscular, subcutaneous, or intravenous administration. Preferably,the route of administration is oral administration.

For oral administration, the pharmaceutical composition can beformulated by mixing the active compound with a pharmaceuticallyacceptable carrier which is well known in the art. With these carriers,the compounds can be formulated into tablets, pills, troches, dragees,capsules, liquids, gels, slurries, suspensions or the like for oraladministration to a patient. For example, for a pharmaceuticalcomposition for oral administration, a tablet can be obtained by thefollowing way: combining the active ingredient with one or more solidcarriers, granulating the resulting mixture if necessary, and adding asmall amount of an excipient if necessary to from a mixture or granule,to form a tablet or a tablet core. The tablet core may be combined withan optional enteric coating material, and processed into a form of acoating formulation that is more advantageous for absorption by anorganism such as a human.

The present disclosure further provides an application of the foregoingdescribed compound, or a pharmaceutically acceptable salt thereof inpreparing RORγt receptor inhibitors.

The present disclosure further provides use of a foregoing describedcompound, or a pharmaceutically acceptable salt thereof or theirpharmaceutical compositions as RORγt receptor inhibitors in preparingdrugs for treatment or prevention of RORγt-related diseases.

Preferably, the aforementioned RORγt inhibitor-related diseases areselected from multiple sclerosis, rheumatoid arthritis, collagen-inducedarthritis, psoriasis, inflammatory bowel disease, encephalomyelitis,clonal diseases, asthma, cancer and other inflammation-related diseases.The cancer is preferably prostate cancer.

The present disclosure provides a class of biaryl urea compoundsrepresented by general formula I. Studies have showed that, this classof compounds can effectively inhibit the RORγt protein receptor, therebyregulating the differentiation of Th17 cells and inhibiting theproduction of IL-17, and can be used as a drug for the treatment ofRORγt-mediated inflammation-related diseases.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following embodiments further describe the technical solutions ofthe present disclosure, but the scope of protection of the presentdisclosure is not limited to these embodiments. Modifications orequivalents that do not depart from the inventive concept are intendedto fall within the scope of protection of the present disclosure.

In the process for preparing the target compound provided in the presentdisclosure, the column chromatography adopts the silica gels (300-300mesh) produced by Rushan Sun Desiccant Co., Ltd.; the thin layerchromatography adopts GF254 (0.25 mm); the nuclear magnetic resonancechromatography (NMR) adopts Varian-400 nuclear magnetic resonanceapparatus; and the LC/MS adopts an Agilent Technologi ESI 6120 LC/MSapparatus.

In addition, all operations involving materials that are susceptible tooxidation or hydrolysis are carried out under the nitrogen protection.Unless otherwise stated, the starting materials used herein arecommercially available materials that can be used directly withoutfurther purification.

Example 1(1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea)

Synthesis of Intermediate 1:2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine Step 1:2-bromo-1,3-dichloro-5-nitrobenzene

2,6-dichloro-4-nitroaniline (5 g, 24 mmol), copper bromide (16 g, 72mmol) and acetonitrile (50 mL) were added to a single-mouth bottle,t-butyl nitrite (7.46 g, 72 mmol) was added dropwise while stirringunder ice bath, and then the obtained mixture was subjected to areaction for 6 hours while stirring at a room temperature. After thereaction, the mixture was added with water (100 mL), extracted withethyl acetate (100 mL×2), washed with saturated sodium chloride (100mL), dried over anhydrous sodium sulfate, and concentrated at a reducedpressure to give 6.3 g orange solid, with a yield of 97%.

Step 2: 4-bromo-3, 5-dichloroaniline

At room temperature, 2-bromo-1,3-dichloro-5-nitrobenzene (1 g, 4 mmol),ethanol (6 mL), tetrahydrofuran (1 mL), concentrated hydrochloric acid(1 mL), and stannous chloride (3.78 g, 16 mmol) were added to asingle-mouth bottle, then heated to 50° C. and stirred for a reactionfor 2 hours. After the reaction, the obtained mixture was cooled to roomtemperature, the solvent was dried with rotation under vacuum, and themixture was added with 2N aqueous solution of sodium hydroxide, andextracted by ethyl acetate (100 mL×3). After that, the organic layerswere combined, dried and concentrated under a reduced pressure to givethe crude product (0.86 g), with a yield of 96.7%.

Step 3: 2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine

4-bromo-3,5-dichloroaniline (200 mg, 0.83 mmol),(2-(trifluoromethoxy)benzyl)boronic acid (342 mg, 1.66 mmol),tri-tert-butylphosphine tetrafluoroborate (96 mg, 0.33 mmol), Pd₂dba₃(304 mg, 0.33 mmol), saturated sodium carbonate (1.245 mL, 2.49 mmol),and 1,4-dioxane (4 mL) were added to a microwave tube, and reacted for 4hours under microwave at 120° C. After reaction, the reaction mixturewas concentrated in vacuo to remove the solvent, added with water, andextracted with ethyl acetate, and then the organic layers were combined,and the solvent was dried under a reduced pressure, and separated by asilica gel column (ethyl acetate:petroleum ether=0:100-10:90), to givethe product (yellow solid, 136 mg), with a yield of 59.9%.

Synthesis of Intermediate 2: (4-(ethylsulfonyl)benzyl) methylamine Step1: 4-(ethylsulfonyl)benzonitrile

4-cyanobenzene-1-sulfonyl chloride (1 g, 4.97 mmol), water (15 mL),sodium bicarbonate (835 mg, 9.94 mmol), and sodium sulfite (689 mg, 5.47mmol) were added to a 100 mL single-mouth bottle, and the reactionsolution reacted for 4 hours while stirring at 70° C., and the solventwas spun under a reduced pressure. The crude product was re-dissolvedwith N,N-dimethylformamide (20 mL), ethyl iodide (1.2 mL) was added, andthe reaction mixture was stirred at 70° C. for 4 hours. After themixture was cooled to room temperature, water (30 mL) was added, and theobtained mixture was extracted with ethyl acetate (30 mL×3). The organiclayers were combined, washed with saturated salt solution, dried overanhydrous sodium sulfate, and filtered. After that, the filtrate wasconcentrated in vacuo give a crude product, and the crude product waspurified by a silica gel column (ethyl acetate:petroleum ether=1:4-1:2)to give the product (yellow solid, 630 mg), with a yield of 65.0%. ¹HNMR (400 MHz, CDCl₃) δ 8.04 (d, J=8.5 Hz, 2H), 7.89 (d, J=8.6 Hz, 2H),3.16 (q, J=7.4 Hz, 2H), 1.30 (t, J=7.4 Hz, 3H).

Step 2: (4-(ethylsulfonyl)benzyl) methylamine

4-(ethylsulfonyl)benzonitrile (630 mg, 3.23 mmol), methanol (10 mL), andPd/C (100 mg, 10%) were added to a 25 mL single-mouth bottle. Thereaction solution was stirred at room temperature for 1 hour under ahydrogen atmosphere, and then filtered over celite, and the solvent wasdried with rotation under vacuum to give the product (white solid, 500mg), with a yield of 77.9%. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.3 Hz,2H), 7.53 (d, J=8.2 Hz, 2H), 3.99 (s, 2H), 3.10 (d, J=7.4 Hz, 2H), 1.27(t, J=7.4 Hz, 3H).

Synthesis of Compound1-(2,6-dichloro-2′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (48 mg,0.15 mmol), dichloromethane (2 mL), and DIEA (38.7 mg, 0.3 mmol) wereadded to a 25 mL single-mouth bottle, and stirred for 5 min under icebath, and then triphosgene (13 mg, 0.05 mmol) was added, and thereaction was continued under ice bath for 30 min, and then(4-(ethylsulfonyl)benzyl)methylamine (30 mg, 0.15 mmol) was added, andthe reaction was continued under ice bath for 30 min, then at roomtemperature overnight. The obtained mixture was added with H₂O (10 mL),and was extracted with dichloromethane (10 mL×3). The organic layerswere combined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo obtain a crude product. The crude product wasseparated by preparative thin layer chromatography(dichloromethane:methanol=50:1) to give the product of1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,r-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl) urea (white solid, 26 mg),with a yield of 31.7%. 1H NMR (400 MHz, CDCl₃) δ 7.67-7.65 (d, J=8.4 Hz,2H), 7.56 (s, 2H), 7.54 (s, 1H), 7.49-7.43 (m, 1H), 7.39-7.34 (m, 4H),7.26-7.22 (m, 1H), 6.08-6.05 (t, J=6.0 Hz, 1H), 4.51-4.50 (d, J=6.0 Hz,2H), 3.18-3.13 (q, J=7.4 Hz, 2H), 1.31-1.27 (t, J=7.4 Hz, 3H). MS (ESI)m/z: 546.7 (MH+).

Example 2: (1-([1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea)

(4-(ethylsulfonyl)benzyl)methylamine (50 mg, 0.30 mmol), DCM (2 mL), andDIEA (77.4 mg, 0.6 mmol) were added to a 25 mL single-mouth bottle andstirred under ice bath condition for 5 min, and then triphosgene (26 mg,0.10 mmol) was added, and the reaction was continued under ice bath for30 min, and then 4-biphenylamine (60 mg, 0.30 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=1:1) to give the product of1-([1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea (white solid,16 mg), with a yield of 22.8%. ¹H NMR (400 MHz, DMSO) δ 7.83 (d, J=7.9Hz, 2H), 7.64-7.51 (m, 7H), 7.48 (d, J=8.2 Hz, 2H), 7.41 (t, J=7.7 Hz,2H), 7.28 (t, J=7.5 Hz, 1H), 6.81 (s, 1H), 4.40 (s, 2H), 3.24 (d, J=7.4Hz, 2H), 1.06 (t, J=7.2 Hz, 3H). MS (ESI) m/z: 394.9 (MH+).

Example 3:(1-(2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea)

Step 1: 2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine

4-chloro-3-bromoaniline (500 mg, 2.43 mmol),2-trifluoromethoxyphenylboronic acid (649 mg, 3.15 mmol), Pd₂(dppf)Cl₂(69 mg, 0.12 mmol), potassium carbonate (1.01 g, 7.29 mmol), andacetonitrile/water (4 mL/1 mL) were added to a microwave tube, afterbeing nitrogen sparged for 5 minutes, the mixture was stirred and heatedto 100° C. for 2 hours under microwave, then the resulting mixture waswashed with saturated ammonium chloride (20 mL), and separated through asilica gel column (eluent petroleum ether:ethyl acetate=10:1-5:1) togive the product of2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (yellow oil,610 mg), with a yield of 88.5%. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.35 (m,1H), 7.36-7.28 (m, 3H), 7.06-7.04 (d, J=8.2 Hz, 1H), 6.81-6.80 (d, J=1.9Hz, 1H), 6.64-6.62 (d, J=8.2 Hz, 1H), 3.57 (s, 2H). MS (ESII) m/z: 288.0(MH+).

Step 2:1-(2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea

2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (50 mg, 0.17mmol), dichloroethane (2 mL), and DIEA (45 mg, 0.35 mmol) were added toa 25 mL three-necked bottle, and stirred under ice bath for 5 min, andthen triphosgene (18.6 mg, 0.06 mmol) was added, and the reaction wascontinued under ice bath for 30 min. Then(4-(ethylsulfonyl)benzyl)methylamine (37.8 mg, 19 mmol) was added, andthe reaction was continued under ice bath for 30 min, then at roomtemperature overnight. After the reaction, H₂O (10 mL) was added, andthe mixture was extracted with dichloromethane (10 mL×3). The organiclayers were combined, washed with saturated sodium chloride (10 mL),dried over anhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo obtain a crude product. The crude product wasseparated by preparative thin layer chromatography(dichloromethane:methanol=20:1) to give the product of1-(2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-yl)-3-(4)(ethylthiosulfonyl)phenyl)urea (white solid, 15 mg), with a yield of16.8%. ¹H NMR (400 MHz, CD₃OD) δ 7.90-7.88 (d, J=8.3 Hz, 2H), 7.72 (d,J=2.0 Hz, 1H), 7.62-7.60 (d, J=8.1 Hz, 2H), 7.53-7.43 (m, 1H), 7.44-7.36(m, 2H), 7.37-7.29 (m, 2H), 7.19-7.17 (d, J=8.4 Hz, 1H), 4.53 (s, 2H),3.21-3.17 (q, J=7.4 Hz, 2H), 1.23-1.19 (t, J=7.4 Hz, 3H). MS (ESI) m/z:513.1 (MH+).

Example 4(1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(methylsulfonyl)benzyl)urea)

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (87 mg,0.27 mmol), DCM (3 mL), and DIEA (104 mg, 0.81 mmol) were added to 25 mLsingle-mouth bottle and stirred under ice bath for 5 min, and thentriphosgene (27 mg, 0.09 mmol) was added, and the reaction was continuedunder ice bath for 30 min, then (4-(methylsulfonyl)benzyl)methylamine(59 mg, 0.27 mmol) was added, and the ice bath is continued for 30 min,then leaving the reaction overnight at room temperature. H₂O (10 mL) wasadded, and the mixture was extracted with dichloromethane (10 mL×3). Theorganic layers were combined, washed with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, and filtered, and the filtratewas concentrated in vacuo to obtain a crude product. The crude productwas separated by preparative thin layer chromatography(dichloromethane:methanol=50:1) to give the product of1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(methylsulfonyl)benzyl)urea(white solid, 5 mg), with a yield of 3.47%. ¹H NMR (400 MHz, CDCl₃) δ7.73-7.71 (d, J=8.2 Hz, 2H), 7.54 (s, 2H), 7.51-7.42 (m, 2H), 7.41-7.33(m, 4H), 7.27-7.23 (m, 2H), 6.02-5.99 (t, J=6.1 Hz, 1H), 4.49-4.48 (d,J=5.7 Hz, 2H), 3.09 (s, 3H). MS (ESI) m/z: 531.0 (M−1).

Example 5(1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)N-methylbenzenesulfonamide)

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (97 mg, 0.3mmol), DCM (10 mL), and DIEA (77 mg, 0.6 mmol) were added to a 50 mLsingle-mouth bottle and stirred under ice bath for 5 min, thentriphosgene (35 mg, 0.12 mmol) was added, and the reaction was continuedunder ice bath for 30 min, and then4-(aminomethyl)-N-methylbenzenesulfonamide (72 mg, 0.36 mmol) was added,and the reaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (20 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by a silica gel column (petroleum ether:ethylacetate=100:1-20:1) to give the product of4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)-N-methylbenzenesulfonamide(white solid, 130 mg), with a yield of 79.3%. ¹H NMR (400 MHz, DMSO) δ9.20 (s, 1H), 7.74-7.72 (d, J=8.2 Hz, 2H), 7.66 (s, (H, 2H),7.44-7.32-4.38 (d, J=5.7 Hz, 2H), 2.38-2.37 (d, J=4.8 Hz, 3H). MS (ESI)m/z: 547.8 (M+1).

Example 6:(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzenesulfonamide)

Step 1: 4-cyanobenzenesulfamide

Aqueous ammonia (13 mL, 194 mmol, 28%) was added to a 50 mL single-mouthbottle, 4-cyanobenzenesulfonyl chloride (4 g, 19.4 mmol) was dissolvedin tetrahydrofuran (5 mL) and added dropwise to the reaction solution inthe bottle to perform reaction for 2 hours at room temperature. Water(20 mL) was added, and the mixture was extracted with ethyl acetate (20mL×3). The organic layers were combined, dried over anhydrous sodiumsulfate, and and the solvent was dried with rotation under vacuum togive the product of 4-cyanobenzenesulfamide (white solid, 3.4 g), with ayield of 94%. ¹H NMR (400 MHz, DMSO) δ 8.06 (d, J=8.5 Hz, 2H), 7.96 (d,J=8.6 Hz, 2H), 7.65 (s, 2H). MS (ESI) m/z: 180.9 (M+1).

Step 2: 4-(aminomethyl)benzenesulfonamide

4-cyanobenzenesulfamide (500 mg, 2.74 mmol), methanol (3 mL),tetrahydrofuran (1 mL), aqueous ammonia (0.5 mL) and Raney Ni (100 mg)were added to a 20 mL single-mouth bottle, and the mixture reacted atroom temperature for 30 min under the hydrogen atmosphere, filtered andconcentrated in vacuo to give the product of4-(aminomethyl)benzenesulfonamide (white solid, 420 mg), with a yield of82.2%. ¹H NMR (400 MHz, DMSO) δ 7.74 (d, J=8.0 Hz, 2H), 7.50 (d, J=7.9Hz, 2H), 7.29 (s, 2H), 3.77 (s, 2H). MS (ESI m/z: 187.0 (M−1).

Step 3:4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzenesulfonamide

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (177 mg,0.55 mmol), DCM (4 mL), and DIEA (212 mg, 1.65 mmol) were added to a 25mL single-mouth bottle, and stirred under ice bath for 5 min, and thentriphosgene (58.8 mg, 0.20 mmol) was added, and the reaction wascontinued under ice bath for 30 min, then4-(aminomethyl)benzenesulfonamide (110 mg, 0.6 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=4:1) to give the product (white solid, 150 mg), witha yield of 47.6%. ¹H NMR (400 MHz, CD₃OD) δ 7.86 (d, J=8.3 Hz, 2H), 7.58(s, 2H), 7.53-7.47 (m, 3H), 7.43-7.36 (m, 2H), 7.28 (d, J=7.5 Hz, 1H),4.47 (s, 2H). MS (ESI) m/z: 531.7 (M−1).

Example 7(N-((4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)sulfonyl)acetamide)

4-((3,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzenesulfonamide(77 mg, 0.14 mmol), methylene chloride (5 mL), acetic anhydride (17.5mg, 0.17 mmol), and triethylamine (17.3 mg, 0.17 mmol) were added to a25 mL single-mouth bottle to react for 2 hours at room temperature whilestirring, then methylene chloride (10 mL) was added, and the mixture waswashed with saturated ammonium chloride (10 mL). The organic layer wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=2:1) to give the product (white solid, 52 mg), witha yield of 62.6%. ¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J=8.3 Hz, 2H), 7.59(s, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H), 7.45-7.41 (m,1H), 7.40-7.36 (m, 1H), 7.29 (d, J=6.3 Hz, 1H), 4.49 (s, 2H), 1.94 (s,3H). MS (ESI m/z: 573.5 (M−1).

Example 8(N-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methanesulfonamide)

Step 1: N-(4-cyanobenzyl) methane sulfonamide

p-cyanoaniline (2 g, 16.9 mmol), pyridine (2.67 g, 33.8 mmol) anddichloromethane (10 mL) were added to a 25 mL single-mouth bottle, andmethanesulfonyl chloride (2.12 g, 18.6 mmol) was added dropwise whilestirring to continue stirring 2 hours at room temperature. Water (50 mL)was added, and the obtained mixture was extracted with ethyl acetate (50mL×3), and washed with saturated sodium chloride. The organic layer wasdried over anhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to give the product (white solid, 2.5 g), with ayield of 78.1%. ¹H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 7.76 (d, J=8.6Hz, 2H), 7.30 (d, J=8.6 Hz, 2H), 3.11 (s, 3H).

Step 2: N-(4-(aminomethyl)benzyl)methane sulfonamide

N-(4-cyanobenzyl) methane sulfonamide (100 mg, 0.51 mmol), methanol (10mL), aqueous ammonia (0.5 mL, 28%) and Raney Ni (100 mg) were added to a25 mL single-mouth bottle to react for 30 minutes at room temperaturewhile stirring, and the obtained mixture was filtered through celite andconcentrated in vacuo to give the product (white solid, 95 mg), with ayield of 93.1%. ¹H NMR (400 MHz, DMSO) δ 7.25 (s, 2H), 7.12 (d, J=7.9Hz, 2H), 3.14 (s, 2H), 2.89 (s, 3H). MS (ESI) m/z: 198.9 (M−1).

Step 3N-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methanesulfonamide

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), DCM (4 mL), and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, stirred for 10 min under ice bath, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 30 min, and then N-(4-(aminomethyl)benzyl)methanesulfonamide (74 mg, 0.37 mmol) was added, and the reaction was continuedunder ice bath for 30 min, then at room temperature overnight. H₂O (10mL) was added, and the obtained mixture was washed with saturatedammonium chloride, and extracted with dichloromethane (10 mL×3). Theorganic layers were combined, washed with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, and filtered, and the filtratewas concentrated in vacuo to obtain a crude product. The crude productwas separated by preparative thin layer chromatography(dichloromethane:methanol=20:1) to give the product (white solid, 120mg), with a yield of 70.0%. ¹H NMR (400 MHz, CD₃OD) δ 7.56 (s, 2H), 7.49(t, J=28 Hz, 1H), 7.44-7.35 (m, 2H), 7.35-7.25 (m, 3H), 7.25-7.16 (m,2H), 4.34 (s, 2H), 2.90 (s, 3H). MS (ESI) m/z: 545.7 (M−1).

Example 9(1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonimidoyl)benzyl)urea)

Step 1: (4-(ethylsulfinyl)benzyl)methylamine

4-(ethylsulfinyl)benzonitrile (228 mg, 1.37 mmol), methanol (10 mL),aqueous ammonia (0.5 mL, 28%) and Raney Ni (100 mg) were added to a 25mL single-mouth bottle. The reaction mixture was stirred at roomtemperature for 1 hour, and filtered through celite, and the solvent wasdried with rotation under vacuum to give the product (white solid, 200mg), with a yield of 98.3%. MS (ESI) m/z: 184.1 (MH+).

Step 2:1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfinyl)benzyl)urea

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (200 mg,0.62 mmol), dichloromethane/N,N-dimethylformamide (4 mL/2 mL) and DIEA(239 mg, 1.86 mmol) were added to a 25 mL single-mouth bottle, stirredfor 10 min under ice bath, and then triphosgene (65 mg, 0.22 mmol) wasadded, and the reaction was continued under ice bath for 30 minutes, andthen (4-(ethylsulfinyl)benzyl)methanamine (136 mg, 0.74 mmol) was added,and the reaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the obtained mixturewas washed with saturated ammonium chloride, and extracted withdichloromethane (10 mL×3). The organic layers were combined, washed withsaturated sodium chloride (10 mL), dried over anhydrous sodium sulfate,and filtered, and the filtrate was concentrated in vacuo to obtain acrude product. The crude product was separated by preparative thin layerchromatography (petroleum ether:ethyl acetate=1: 2-1:1) to give theproduct (white solid, 137 mg), with a yield of 41.6%. ¹H NMR (400 MHz,CDCl₃) δ 8.51 (s, 1H), 7.59 (s, 2H), 7.50-7.43 (m, 1H), 7.44-7.30 (m,6H), 7.27 (s, 1H), 4.49 (s, 2H), 3.01-2.86 (m, 2H), 1.23 (t, J=7.4 Hz,3H). MS (ESI) m/z: 530.7 (MH+).

Step 3:1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfonimido)benzyl)urea

1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(4-(ethylsulfinyl)benzyl)urea(140 mg, 0.25 mmol), trifluoroacetamide (58 mg, 0.52 mmol), magnesiumoxide (42 mg, 1.04 mmol), rhodium acetate (2.8 mg, 2.5 mol %),iodobenzene tetraacetate (128 mg, 0.4 mmol), and dichloromethane (10 mL)were added to a 25 mL single-mouth bottle, and reacted at roomtemperature overnight. And the mixture was concentrated in vacuo toremove the solvent, then added with methanol (1 mL) and potassiumcarbonate (179 mg, 1.3 mmol), and stirred for 2 hours continuously atroom temperature. After the solvent was removed by concentration invacuo, the crude product was separated by a silica gel column(dichloromethane:methanol=50:1), to give the product (white solid, 70mg), with a yield of 50.4%. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1H), 7.75(d, J=6.9 Hz, 2H), 7.55 (s, 2H), 7.45 (t, J=7.1 Hz, 1H), 7.39-7.28 (m,4H), 7.22 (d, J=6.7 Hz, 1H), 6.68 (s, 1H), 4.44 (d, J=4.4 Hz, 2H), 3.20(s, 2H), 2.77 (s, 1H), 1.25 (d, J=7.5 Hz, 3H). MS (ESI) m/z: 545.7(MH+).

Example 104-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)-N-(methylsulfonyl)benzamide

Step 1: 4-cyano-N-(methylsulfonyl)benzamide

p-cyanobenzoic acid (1 g, 6.8 mmol), thionyl chloride (0.5 mL), andN,N-dimethylformamide (2 drops) were added to a 25 mL single-mouthbottle, and heated to react for 2 hours at 70° C., and thionyl chloridewas concentrated under a reduced pressure. The crude product wasdissolved in dichloromethane (20 mL), triethylamine (2.06 g, 20 mmol),methane sulfonamide (770 mg, 8.2 mmol) were added, and the mixture wasstirred at room temperature overnight. Then H₂O (20 mL) was added, andthe obtained mixture washed with saturated ammonium chloride, andextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by a silica gel column (dichloromethane:methanol=20:1) to givethe product (yellow solid, 400 mg), with a yield of 26.3%. ¹H NMR (400MHz, DMSO) δ 8.04 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.3 Hz, 2H), 3.10 (s,3H). MS (ESI) m/z: 222.9 (M−1).

Step 2: 4-(aminomethyl)-N-(methylsulfonyl)benzamide

4-cyano-N-(methylsulfonyl)benzamide (400 mg, 1.79 mmol), methanol (2mL), aqueous ammonia (0.5 mL, 28%) and Raney Ni (100 mg) were added to a25 mL single-mouth bottle. The reaction mixture was stirred at roomtemperature for 30 minutes under hydrogen atmosphere at an atmosphericpressure, then filtered through celite, and the solvent was dried withrotation under vacuum to give the product (white solid, 360 mg), with ayield of 78.7%. MS (ESI) m/z: 226.9 (M−1).

Step 3(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)-N-(methylsulfonyl)benzamide

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), DCM (4 mL), and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, and stirred for 10 min under ice bath, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 30 minutes, and then4-(aminomethyl)-N-(methylsulfonyl)benzamide (74 mg, 0.37 mmol) wasadded, and the reaction was continued under ice bath for 30 min, then atroom temperature overnight. H₂O (10 mL) was added, and the obtainedmixture was washed with saturated ammonium chloride, and extracted withdichloromethane (10 mL×3). The organic layers were combined, washed withsaturated sodium chloride (10 mL), dried over anhydrous sodium sulfate,and filtered, and the filtrate was concentrated in vacuo to obtain acrude product. The crude product was separated by preparative thin layerchromatography (dichloromethane:methanol=20:1) to give the product(white solid, 70 mg), with a yield of 39.1%. ¹H NMR (400 MHz, CD₃OD) δ7.88 (d, J=8.2 Hz, 2H), 7.59 (s, 2H), 7.55-7.49 (m, 1H), 7.49-7.45 (m,2H), 7.45-7.36 (m, 2H), 7.29 (dd, J=7.6, 1.5 Hz, 1H), 4.48 (s, 2H), 3.34(d, J=1.7 Hz, 3H). MS (ESI) m/z: 575.6 (MH⁺).

Example 11:(1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-((5-(ethylsulfonyl)pyridine-2-yl)methyl)urea

Step 1: 5-(ethylthio) pyridinecarbonitrile

5-bromo-2-pyridinecarbonitrile (940 mg, 5.14 mmol), ethanethiol (505 mg,6.01 mmol), potassium carbonate (981 mg, 7.11 mmol), and NMP (10 mL)were added to a 50 mL single-mouth bottle. The obtained mixture reactedat room temperature while stirring overnight. Water (20 mL) was added,and the mixture was extracted with ethyl acetate (30 mL×3). The organiclayer was concentrated in vacuo to give the product of 5-(ethylthio)pyridinecarbonitrile (900 mg), with a yield of 100%. MS (ESI) m/z: 165.1(MH+).

Step 2: 5-(ethylsulfonyl)-2-pyridinecarbonitrile

5-(ethylthio) pyridinecarbonitrile (800 mg, 4.88 mmol) anddichloromethane (20 mL) were added to a 25 mL single-mouth bottle, andstirred for 10 min under ice bath, and mCPBA (1.84 g, 10.7 mmol) wasadded to the reaction mixture in portions, leaving the reaction at roomtemperature overnight. The reaction mixture was washed with 2N sodiumcarbonate solution, and the organic layer was concentrated in vacuo andpassed through a silica gel column (petroleum ether:ethylacetate=2:1-1:1) to give the product (900 mg), with a yield of 90.0%. ¹HNMR (400 MHz, CDCl₃) δ 9.18 (d, J=1.2 Hz, 1H), 8.37 (dd, J=8.0, 1.8 Hz,1H), 7.93 (d, J=8.0 Hz, 1H), 3.21 (q, J=7.4 Hz, 2H), 1.34 (t, J=7.4 Hz,3H). MS (ESI) m/z: 197.1 (MH+).

Step 3: (5-(ethylsulfonyl)-pyridine-2-yl)methylamine

5-(ethylsulfonyl) 2-pyridinecarbonitrile (200 mg, 1 mmol), methanol (10mL) and Pd/C (100 mg, 10%) were added to a 25 mL single-mouth bottle.The reaction mixture was stirred at room temperature for 30 min, andfiltered through celite, and the solvent was dried with rotation undervacuum to give the product (white solid, 110 mg), with a yield of 53.9%.MS (ESI) m/z: 201.1 (MH+).

Step 4:1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(5-(ethylsulfonyl)-2-pyridyl)urea

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), DCM (4 mL), and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, and stirred for 10 min under ice bath. Thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 30 min, and then (5-(ethylsulfonyl)pyridine-2-yl)methylamine (74 mg, 0.37 mmol) was added, and the reactionwas continued under ice bath for 30 min, then at room temperatureovernight. H₂O (10 mL) was added, and the obtained mixture was washedwith saturated ammonium chloride, and extracted with dichloromethane (10mL×3). The organic layers were combined, washed with saturated sodiumchloride (10 mL), dried over anhydrous sodium sulfate, and filtered, andthe filtrate was concentrated in vacuo to obtain a crude product. Thecrude product was separated with preparative thin layer chromatography(dichloromethane:methanol=20:1) to give the product (white solid, 70mg), with a yield of 39.1%. ¹H NMR (400 MHz, CD₃OD) δ 8.98 (d, J=2.0 Hz,1H), 8.27 (dd, J=8.3, 2.3 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.60 (s, 2H),7.56-7.47 (m, 1H), 7.46-7.36 (m, 2H), 7.29 (dd, J=7.6, 1.5 Hz, 1H), 4.64(s, 2H), 3.28 (dd, J=14.7, 7.3 Hz, 2H), 1.24 (dd, J=10.0, 4.8 Hz, 3H).MS (ESI) m/z: 547.7 (MH+).

Example 12:(1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-((5-(methylsulfonyl)pyridine-2-yl)methyl)urea

Step 1: 5-ethylsulfonyl-2-pyridinecarbonitrile

6-cyanopyridine-3-sulfonyl chloride (1 g, 4.9 mmol), water (15 mL),sodium bicarbonate (823 mg, 9.8 mmol) and sodium sulfite (679 mg, 5.39mmol) were added to a 50 mL single-mouth bottle. The reaction mixturewas stirred at 70° C. for subjecting to a reaction overnight, and thesolvent was dried with rotation under a reduced pressure. The crudeproduct was dissolved again with N,N-dimethylformamide (20 mL), thenmethyl iodide (2.08 g, 14.7 mmol) was added, and the reaction mixturewas stirred at 70° C. for 4 hours. After being cooled to roomtemperature, the reaction mixture was added with water (30 mL), andextracted with ethyl acetate (30 mL×3). The organic layers werecombined, washed with water for five times, washed once with saturatedsodium chloride, dried over anhydrous sodium sulfate, and filtered, andthe filtrate was concentrated under a reduced pressure to obtain a crudeproduct. The crude product was separated by a silica gel column (ethylacetate:petroleum ether=1.4-1.2), to give the product (white solid, 450mg), with a yield of 50.2%. ¹H NMR (400 MHz, CDCl₃) δ 9.24 (d, J=1.5 Hz,1H), 8.41 (dd, J=8.1, 2.2 Hz, 1H), 7.93 (dd, J=8.1, 0.6 Hz, 1H), 3.17(s, 3H). MS (ESI) m/z: 183.1 (MIFF).

Step 2: 5-(methylsulfonyl) 2-pyridinemethylamine

5-ethylsulfonyl-2-pyridinecarbonitrile (350 mg, 1.92 mmol), methanol (2mL), concentrated hydrochloric acid (5 drops) and Pd/C (35 mg) wereadded to a 25 mL single-mouth bottle. The reaction mixture was stirredat room temperature for 30 minutes while introducing hydrogen gas, andfiltered over celite, and the solvent was dried with rotation undervacuum to give the product (266 mg), with a yield of 74.5%. MS (ESI)m/z: 187.1 (MH+).

Step 3:1-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-(5-(methylsulfonyl)-2-pyridyl)urea

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL), and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle under ancondition of nitrogen protection, and stirred for 5 min under ice bath,and then triphosgene (35 mg, 0.11 mmol) was added, and the reaction wascontinued under ice bath for 10 minutes, and then 5-(methylsulfonyl)2-pyridylmethylamine (63 mg, 0.34 mmol) was added, and the reaction wascontinued under ice bath for 30 min. H₂O (10 mL) was added, and theobtained mixture was washed with saturated ammonium chloride, extractedwith dichloromethane (10 mL×3). The organic layers were combined, washedwith saturated sodium chloride (10 mL), dried over anhydrous sodiumsulfate, and filtered, and the filtrate was concentrated in vacuo toobtain a crude product. The crude product was separated with preparativethin layer chromatography (dichloromethane:methanol=30:1) to give theproduct (white solid, 94 mg), with a yield of 56.3%. ¹H NMR (400 MHz,CD₃OD) δ 9.03 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.3, 2.3 Hz, 1H), 7.66 (d,J=8.3 Hz, 1H), 7.60 (s, 2H), 7.55-7.47 (m, 1H), 7.45-7.35 (m, 2H), 7.28(dd, J=7.6, 1.4 Hz, 1H), 4.63 (s, 2H), 3.19 (s, 3H). MS (ESI) m/z: 533.8(MH+).

Example 13:(6-((3-(2,6-dichloro-T-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)-N-methylpyridine-3sulfonamide

Step 1: 6-cyanopyridine-3-sulfonyl chloride

Water (90 mL) was added to a 500 mL single-mouth bottle A and stirredfor 10 min under ice bath, then thionyl chloride (17 mL) was addeddropwise slowly, after the addition, the obtained is subjected to areaction for 8 hours at room temperature, and then cuprous chloride (66mg, 0.67 mmol) was added, then subjecting to an ice bath.

5-aminopyridine carbonitrile (4.99 g, 41.9 mmol) and concentratedhydrochloric acid (50 mL) were added to another 500 mL single-mouthbottle B, stirred to be cooled under ice bath for 10 minutes, and thenthe aqueous solution (25 mL) of sodium nitrite (4.11 g, 59.6 mmol) wasadded dropwise, after the addition, the obtained mixture is subjected toa reaction under ice bath for 20 minutes. The reaction mixture in thesingle-mouth bottle B were added to the single-mouth bottle A under icebath, after the addition, the obtained mixture was subjected to areaction for another 1 hour under ice bath, and a large amount of brownsolid was precipitated, which was subjected to filtration, washed withwater (125 mL×3), and dried under a vacuum condition to give the product(brown solid, 3.7 g), with a yield of 43.5%. MS (ESI) m/z: 202.9(MI-1+).

Step 2: 6-cyano-N-methylpyridine-3-sulfonamide

6-cyanopyridine-3-sulfonyl chloride (1 g, 4.9 mmol), tetrahydrofuran (10mL), and methylamine in ethanol (5.35 g, 49 mmol) were added to a 25 mLsingle-mouth bottle, and reacted at a room temperature for 10 minutes,and the obtained mixture was concentrated in vacuo to remove thesolvent, and was separated by a silica gel column to give the product(550 mg), with a yield of 57.8%. ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H),(dd, J=8.1, 2.1 Hz, 1H), 7.88 (d, J=8.1 Hz, 1H), 4.72 (s, 1H), 2.78 (d,J=5.2 Hz, 3H). MS (ESI) m/z: 198.1 (MH+).

Step 3: 6-(aminomethyl)-N-methylpyridine-3-sulfonamide

6-cyano-N-methylpyridine-3-sulfonamide (250 mg, 1.27 mmol), methanol (4mL), concentrated hydrochloric acid (5 drops) and Pd/C (25 mg, 60% inoil) were added to a 25 mL single-mouth bottle. The reaction mixture wasstirred for 30 min at room temperature, filtered over celite, and thenthe solvent was dried with rotation under vacuum, and the product wasused in the next step directly. MS (ESI) m/z: 202.1 (MH+).

Step 46-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)-N-methylpyridine-3-sulfonamide

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL) and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredunder ice bath for 5 minutes with the nitrogen protection, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then6-(aminomethyl)-N-methylpyridine-3-sulfonamide (74 mg, 0.37 mmol) wasadded, and the reaction was continued under ice bath for 30 min. H₂O (10mL) was added, and the obtained mixture was washed with saturatedammonium chloride, and extracted with dichloromethane (10 mL×3). Theorganic layers were combined, washed with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, and filtered, and the filtratewas concentrated in vacuo to obtain a crude product. The crude productwas separated by a silica gel column (petroleum ether:ethyl acetate=1:2)to give the product (white solid, 41 mg), with a yield of 29.4%. ¹H NMR(400 MHz, CD₃OD) δ 8.91 (d, J=1.8 Hz, 1H), 8.18 (dd, J=8.3, 2.2 Hz, 1H),7.61 (d, J=9.9 Hz, 3H), 7.51 (td, J=8.1, 1.6 Hz, 1H), 7.44-7.37 (m, 2H),7.29 (dd, J=7.6, 1.4 Hz, 1H), 4.61 (s, 2H), 2.55 (d, J=4.9 Hz, 3H). MS(ESI) m/z: 548.8 (MH+).

Example 14:4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzoicacid

Step 1:4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)methylbenzoate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), DCM (5 mL) and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, and stirred for 5 min under ice bath, and thentriphosgene (33 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 30 min, and then 4-methyl aminomethylbenzoate (56 mg,0.34 mmol) was added, and the reaction was continued under ice bath for30 min, then at room temperature overnight. H₂O (10 mL) was added, andthe mixture was extracted with dichloromethane (10 mL×3). The organiclayers were combined, washed with saturated sodium chloride (10 mL),dried over anhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=10:1) to give the product (white solid, 80 mg), witha yield of 50.3%. ¹NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.1 Hz, 2H), 7.82(s, 1H), 7.49-7.41 (m, 1H), 7.39 (s, 2H), 7.36-7.30 (m, 2H), 7.22 (d,J=8.1 Hz, 2H), 7.17 (d, J=7.6 Hz, 1H), 6.06 (s, 1H), 4.36 (d, J=4.9 Hz,2H), 3.88 (s, 3H). MS (ESI) m/z: 512.7 (M−1).

Step 2:4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzoicacid

4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl)-4-yl]ureido)methyl)methylbenzoate (80 mg, 0.16 mmol), lithium hydroxide (19 mg, 0.48 mmol),ethanol (1 mL) and water (0.3 mL) were added to a 25 mL single-mouthbottle for reaction for 2 hours at room temperature. After confirmingthe completion of the reaction of materials by TLC, the mixture wasadjusted to pH 3 with 2N hydrochloric acid, and then extracted withethyl acetate (10 mL×3). The organic layers were concentrated in vacuoto obtain a crude product, and the crude product was separated bypreparative thin layer chromatography for many times to give the product(white solid, 18 mg), with a yield of 24.3%. ¹H NMR (400 MHz, CD₃OD) δ8.01 (d, J=8.2 Hz, 2H), 7.60 (s, 2H), 7.52 (t, J=7.0 Hz, 1H), 7.47-7.39(m, 4H), 7.30 (d, J=7.5 Hz, 1H), 4.48 (s, 2H). MS (ESI) m/z: 496.7(M−1).

Example 152-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)aceticacid

Step 1: methyl 4-aminomethylphenylacetate

P-methyl cyanobenzoate (200 mg, 1.14 mmol), methanol (2 mL), a smallamount of Pd/C and 2 drops of concentrated hydrochloric acid were addedto a 25 mL single-mouth bottle, and stirred to react at room temperaturefor 3 hours under a hydrogen atmosphere at atmospheric pressure. Afterconfirming reaction completion by TLC, the mixture was filtered, andconcentrated in vacuo to give the product of methyl4-aminomethylphenylacetate (white solid, 178 mg), with a yield of 74.2%.¹H NMR (400 MHz, DMSO) δ 8.22 (s, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.30 (d,J=8.1 Hz, 2H), 3.98 (s, 2H), 3.71 (s, 2H), 3.61 (s, 3H). MS (ESI) m/z:180.1 (M+1).

Step 22-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (40 mg,0.12 mmol), DCM (3 mL), and DIEA (31 mg, 0.24 mmol) were added to a 25mL single-mouth bottle, and stirred for 5 min under ice bath, and thentriphosgene (15 mg, 0.05 mmol) was added, and the reaction was continuedunder ice bath for 30 min, and then 4-aminomethylphenylacetic acidmethyl ester (27 mg, 0.15 mmol) was added, and the reaction wascontinued under ice bath for 30 min, then at room temperature overnight.H₂O (10 mL) was added, and the mixture was extracted withdichloromethane (10 mL×3). The organic layers were combined, washed withsaturated sodium chloride (10 mL), dried over anhydrous sodium sulfate,and filtered, and the filtrate was concentrated in vacuo to obtain acrude product. The crude product was separated by preparative thin layerchromatography (dichloromethane:methanol=50:1) to give the product of2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (white solid, 25 mg), with a yield of 38.5%. ¹H NMR (400 MHz,CDCl₃) δ 7.60 (s, 1H), 7.48-7.42 (t, J=7.1 Hz, 1H), 7.42 (s, 2H),7.39-7.31 (m, 2H), 7.24-7.22 (d, J=6.5 Hz, 1H), 7.20-7.11 (m, 4H), 5.66(s, 1H), 4.27-4.25 (d, J=52 Hz, 2H), 3.71 (s, 3H), 3.63 (s, 2H), 1.87(s, 1H). MS (ESI) m/z: 527.1 (MH+).

Step 32-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)aceticacid

2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (25 mg, 0.047 mmol), sodium hydroxide (5.7 mg, 0.14 mmol),ethanol (2 mL) and water (0.5 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingthe completion of reaction by TLC, the reaction mixture was adjustedwith 2N hydrochloric acid to pH 3. The mixture was extracted with ethylacetate (10 mL×3), and the organic layer was concentrated in vacuo togive the product of2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)acetic acid (white solid, 18 mg), with a yield of 75.0%. ¹H NMR (400MHz, CD₃OD) δ 7.59 (s, 2H), 7.54-7.51 (t, J=7.1 Hz, 1H), 7.44-7.39 (m,2H), 7.33-7.25 (m, 5H), 4.39 (s, 2H), 3.59 (s, 2H). MS (ESI) m/z: 513.1(MH+).

Example 162-(4-((3-(2-chloro-6-cyano-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid

Step 1: 3-chloro-5-cyano-2-bromobenzene

2-amino-3-chloro-5-nitrobenzonitrile (3 g, 15 mmol), copper bromide (4g, 18 mmol) and acetonitrile (50 mL) were added to a 25 mL single-mouthbottle. After the obtained mixture was stirred for 5 min under ice bath,n-pentyl nitrite (6.76 g, 57.8 mmol) was weighed and added toacetonitrile (20 mL), and added dropwise to the mixture under ice bath,and then the reaction was continued under ice bath for 30 minutes. Thereaction mixture was naturally warmed to room temperature and allowed toreact overnight. Water (100 mL) was added, and the reaction mixture wasextracted with ethyl acetate (100 mL×3), washed with water (100 mL),washed with saturated sodium chloride (100 mL), and dried over anhydroussodium sulfate, and the solvent was dried with rotation under vacuum toget a crude product. And then the crude product was separated by asilica gel column to give the product of 3-chloro-5-cyano-2-bromobenzene(yellow solid, 2.3 g), with a yield of 58.4%. ¹H NMR (400 MHz, CDCl₃) δ8.52 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H).

Step 2:6-chloro-4-nitro-2′(trifluoromethoxy)-[1,1′-biphenylyl]-2-carbonitrile

2-bromo-3-chloro-5-nitrobenzonitrile (300 mg, 1.15 mmol),2-trifluoromethoxy phenylboronic acid (355 mg, 1.72 mmol), Pd₂(dba)₃ (11mg, 0.012 mmol), tri-tert-butylphosphonium tetrafluoroborate (10 mg,0.033 mmol), potassium phosphate trihydrate (897 mg, 3.45 mmol) and1,4-dioxane/H₂O (10 mL/1 mL) were added to a microwave tube. The mixturewas nitrogen sparged for 5 min, and stirred and heated to 100° C. for1.5 hours under microwave, and the resulting mixture was washed withsaturated ammonium chloride (20 mL), and separated by silica gel column(petroleum ether:ethyl acetate=30:1) to give the product of6-chloro-4-nitro-2′(trifluoromethoxy)-[1,1′-biphenylyl]-2-carbonitrile(yellow solid, 270 mg), with a yield of 68.7%. ¹H NMR (400 MHz, CDCl₃) δ8.59-8.58 (d, J=2.1 Hz, 1H), 8.54-8.53 (d, J=2.1 Hz, 1H), 7.65-7.62 (t,J=7.1 Hz, 1H), 7.55-7.45 (m, 2H), 7.37-7.35 (d, J=7.5 Hz, 1H).

Step 3:4-amino-6-chloro-2′-(trifluoromethoxy)-[1,1-biphenylyl]-2-carbonitrile

6-chloro-4-nitro-2′(trifluoromethoxy)-[1,1′-biphenylyl]-2-carbonitrile(265 mg, 0.77 mmol), stannous chloride dihydrate (524 mg, 2.31 mmol),ethanol (20 mL), and concentrated hydrochloric acid (2 mL) were added toa 25 mL single-mouth bottle, and heated to react for 3 hours at 60° C.After confirming completion of reaction by TLC, the mixture was cooledto room temperature, added with 2N hydrogen hydroxide solution to adjustits pH to alkaline, and extracted with ethyl acetate (20 mL×3). Theorganic layers were combined, and washed with saturated sodium chloride(30 mL), and the solvent was dried with rotation under vacuum to givethe product of4-amino-6-chloro-2′-(trifluoromethoxy)-[1,1biphenylyl]-2-carbonitrile(white solid, 240 mg), with a yield of 99.6%. ¹H NMR (400 MHz, CDCl₃) δ7.51-7.48 (t, J=7.0 Hz, 1H), 7.43-7.36 (m, 2H), 7.34-7.33 (d, J=6.3 Hz,1H), 6.99 (d, J=2.3 Hz, 1H), 6.92 (d, J=2.3 Hz, 1H), 2.96 (s, 2H).

Step 4:2-(4-((3-(2-chloro-6-cyano-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methyl acetate

4-amino-6-chloro-2′-(trifluoromethoxy)-[1,1-biphenylyl]-2-carbonitrile(80 mg, 0.26 mmol), DCM (4 mL), and DIEA (67 mg, 0.52 mmol) were addedto a 25 mL single-mouth bottle, and stirred for 5 min under ice bath,and then triphosgene (29.7 mg, 0.10 mmol) was added, and the reactionwas continued under ice bath for 30 minutes, and then methyl4-aminomethylphenylacetate (50 mg, 0.28 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=10:1) to give the product of2-(4-((3-(2-chloro-6-cyano-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (white solid, 38 mg), with a yield of 28.8%. ¹H NMR (400 MHz,CDCl₃) δ 7.87-7.78 (m, 2H), 7.54-7.47 (m, 2H), 7.41-7.37 (t, J=7.2 Hz,2H), 7.31-7.29 (d, J=6.5 Hz, 1H), 7.21-7.16 (m, 4H), 5.70 (s, 1H),4.29-4.28 (d, J=Hz, 2H), 3.67 (s, 3H), 3.62 (s, 2H). MS (ESI) m/z: 518.2(MH+).

Step 5:2-(4-((3-(2-chloro-6-cyano-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)acetic acid

2-(4-((3-chloro-6-cyano-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (38 mg, 0.014 mmol), lithium hydroxide monohydrate (9.2 mg, 0.22mmol), ethanol (1 mL), and water (0.3 mL) were added to a 25 mLsingle-mouth bottle, and reacted for 2 hours at room temperature. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethylacetate (10 mL×3). The organic layer was concentrated in vacuo to givethe product of2-(4-((3-(2-chloro-6-cyano-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)aceticacid (white solid, 27 mg), with a yield of 72.9%. ¹H NMR (400 MHz,CD₃OD) δ 7.93-7.92 (d, J=2.1 Hz, 1H), 7.87-7.86 (d, J=2.1 Hz, 1H),7.61-6.57 (t, J=11.1, 4.6 Hz, 1H), 7.51-7.44 (m, 2H), 7.43-7.38 (m, 1H),7.32-7.26 (m, 3H), 7.25-7.23 (d, J=11.0 Hz, 1H), 4.39 (s, 2H), 3.59 (s,2H). MS (ESI) m/z: 504.1 (MH+).

Example 172-(4-((3-(2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)aceticacid

Step 1: 2-bromo-1-chloro-3-methyl-5-nitrobenzene

2-chloro-6-methyl-4-nitroaniline (500 mg, 2.68 mmol), copper bromide(718 mg, 3.22 mmol), and acetonitrile (8 mL) were added to a 25 mLthree-necked bottle and stirred for 5 min under ice bath. Tert-butylnitrite (470 mg, 4.02 mmol) was dissolved in acetonitrile (2 mL), andthen added dropwise to the three-necked bottle, and the mixture wasallowed to warm to room temperature, reacting overnight. H₂O (20 mL) wasadded, and the mixture was extracted with ethyl acetate (20 mL×3). Theorganic layers were combined, and washed with saturated sodium chloride(20 mL), and the solvent was dried with rotation under vacuum, to givethe product of 2-bromo-1-chloro-3-methyl-5-nitrobenzene (yellow solid,650 mg), with a yield of 96.7%. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H),8.01 (s, 1H), 2.57 (s, 3H).

Step 2: 4-bromo-3-chloro-5-methylaniline

2-bromo-1-chloro-3-methyl-5-nitrobenzene (640 mg, 2.56 mmol), stannouschloride dihydrate (2.25 g, 10 mmol), concentrated hydrochloric acid(0.5 mL), ethanol (10 mL) and tetrahydrofuran (4 mL) were added to a 25mL single-mouth bottle, heated to react for 2 hours at 60° C. whilestirring, and then naturally cooled to room temperature. Then water (30mL) and 20% sodium chloride (50 mL) were added, and the mixture wasextracted with ethyl acetate (50 mL×3). The organic layers werecombined, washed with saturated sodium chloride (50 mL), dried overanhydrous sodium sulfate, and filtered, and the solvent was dried withrotation under vacuum, to give the product of4-bromo-3-chloro-5-methylaniline (yellow solid, 540 mg), with a yield of95.9%. ¹H NMR (400 MHz, CDCl₃) δ 6.65 (d, J=2.3 Hz, 1H), 6.47 (s, 1H),3.65 (s, 2H), 2.34 (s, 3H). MS (ESI) m/z: 220.0 (MH+)

Step 3:2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine

4-bromo-3-chloro-5-methylaniline (500 mg, 2.3 mmol), 2-trifluoromethoxyphenylboronic acid (710 mg, 3.5 mmol), Pd₂(dba)₃ (210 mg, 0.23 mmol),tert-butylphosphonium tetrafluoroborate (200 mg, 0.7 mmol), sodiumcarbonate (730 mg, 6.9 mmol), and 1,4-dioxane/water (10 mL/1 mL) wereadded to a microwave tube. The mixture was nitrogen sparged for 5 min,and stirred and heated to 120° C. for 3 hours under microwave, washedwith saturated ammonium chloride (50 mL), and separated by silica gelcolumn (petroleum ether:ethyl acetate=20:1-10:1) to give the product of2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine(yellow solid, 190 mg), with a yield of 27.8%. MS (ESI) m/z: 302.1(MH+). MS (ESI) m/z: 220.0 (MH+).

Step 42-(4-((3-(2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)ethylacetate

2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (30mg, 0.1 mmol) DCM (1 mL) and DIEA (26 mg, 0.2 mmol) were added to a 25mL single-mouth bottle, and stirred for 5 min under ice bath, and thentriphosgene (12 mg, 0.04 mmol) was added, and the reaction was continuedunder ice bath for 30 minutes, and then methyl4-aminomethylphenylacetate (22 mg, 0.12 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the obtained mixturewas extracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography(dichloromethane:methanol=20:1) to give the product of2-(4-((3-(2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)ethylacetate (white solid, 31 mg), with a yield of 62.0%. ¹H NMR (400 MHz,CDCl₃) δ 7.45-7.38 (m, 1H), 7.38-7.30 (m, 3H), 7.22-7.11 (m, 6H), 5.65(s, 1H), 4.28 (s, 2H), 3.68 (s, 3H), 3.60 (s, 2H), 1.95 (s, 3H). MS(ESI) m/z: 5O7.2 (MH+).

Step 5:2-(4-((3-(2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)acetic acid

2-(4-((3-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (30 mg, 0.059 mmol), sodium hydroxide (7.1 mg, 0.177 mmol),ethanol (1 mL), and water (0.3 mL) were added to a 25 mL single-mouthbottle, and reacted for 2 hours at room temperature. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate (10mL×3). The organic layer was concentrated in vacuo to give the productof2-(4-((3-(2-chloro-6-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)acetic acid (white solid, 23 mg), with a yield of 79.3%.¹H NMR (400 MHz, CD₃OD) δ 7.55 (s, 1H), 7.51-7.47 (t, J=1.6, 6.4 Hz,1H), 7.43-7.38 (m, 2H), 7.33-7.22 (m, 5H), 7.19 (s, 1H), 4.39 (s, 2H),3.59 (s, 2H), 2.00 (s, 3H). MS (ESI) m/z: 493.1 (MH+).

Example 182-(4-((3-(2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)aceticacid

Step 1: 2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine

4-chloro-3-bromoaniline (500 mg, 2.43 mmol),2-trifluoromethoxyphenylboronic acid (649 mg, 3.15 mmol), Pd₂(dppf)Cl₂(69 mg, 0.12 mmol), potassium carbonate (1.01 g, 7.29 mmol), andacetonitrile/water (4 mL/1 mL) were added to a microwave tube. Themixture was nitrogen sparged for 5 min, and stirred and heated to 120°C. for 2 hours under microwave, washed with saturated ammonium chloride(20 mL), and separated by silica gel column (petroleum ether:ethylacetate=10:1-5:1) to give the product of2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (yellow oil,610 mg), with a yield of 88.5%. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.35 (m,1H), 7.36-7.28 (m, 3H), 7.06-7.04 (d, J=8.2 Hz, 1H), 6.81-6.80 (d, J=1.9Hz, 1H), 6.64-6.62 (d, J=8.2 Hz, 1H), 3.57 (s, 2H). MS (ESI) m/z: 288.0(MH+)

Step 2:2-(4-((3-chloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate

2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg, 0.34mmol), dichloromethane (4 mL), and DIEA (129 mg, 1 mmol) were added to a25 mL single-mouth bottle, and stirred for 5 min under ice bath, andthen triphosgene (35 mg, 0.12 mmol) was added, and the reaction wascontinued under ice bath for 30 minutes, and then methyl4-aminomethylphenylacetate (73 mg, 0.34 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the obtained mixturewas extracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=2:1) to give the product of2-(4-((3-chloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (white solid, 31 mg), with a yield of 18.1%. MS (ESI) m/z: 493.1(MH+).

Step 3:2-(4-((3-(2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)aceticacid

2-(4-((3-(2-chloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl)-4-urela)methyl)benzyl)methylacetate (30 mg, 0.06 mmol), sodium hydroxide (7.3 mg, 0.18 mmol),ethanol (2 mL) and water (0.5 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate (10mL×3). The organic layer was concentrated in vacuo to give the product(white solid, 23 mg), with a yield of 79.3%. ¹H NMR (400 MHz, CD₃OD) δ7.71-7.70 (d, J=1.9 Hz, 1H), 7.50-7.47 (t, J=7.6, 1H), 7.42-7.36 (m,3H), 7.35-7.23 (m, 6H), 7.18-7.16 (d, J=8.4 Hz, 1H), 4.40 (s, 2H), 3.60(s, 2H). MS (ESI) m/z: 479.1 (MH+).

Example 192-(4-((3-(2,6-difluoro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)aceticacid

Step 1: 2,6-difluoro-2′-trifluoromethoxy-[1,1′-biphenylyl]-4-amine

4-bromo-3, 5-difluoroaniline (500 mg, 2.4 mmol),2-trifluoromethoxybenzeneboronic acid (590 mg, 2.9 mmol), Pd₂(dppf)Cl₂(98 mg, 0.12 mmol), cesium carbonate (2.35 g, 7.2 mmol) andacetonitrile/water (10 mL/1 mL) were added to a microwave tube. Themixture was nitrogen sparged for 5 min, stirred and heated to 120° C.for 1 hour under microwave, washed with saturated ammonium chloride (20mL), and separated by silica gel column (petroleum ether:ethylacetate=50:1) to give the product of2,6-difluoro-2′-trifluoromethoxy-[1,1′-biphenylyl]-4-amine (yellow oil,460 mg), with a yield of 66.3%. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.28 (m,4H), 6.29-6.27 (d, 9.1 Hz, 2H), 3.67 (s, 2H). MS (ESI) m/z: 290.1 (MH+).

Step 22-(4-((3-(2,6-difluoro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methylacetate

2,6-difluoro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (20 mg,0.069 mmol), DCM (1 mL), and DIEA (18 mg, 0.03 mmol) were added to a 25mL single-mouth bottle, and stirred for 5 min under ice bath, and thentriphosgene (10 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 30 minutes, and then methyl4-aminomethylphenylacetate (16 mg, 0.11 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=2:1) to give the product of2-(4-((3-(2,6-difluoro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methylacetate (white solid, 7 mg), with a yield of 20.6%. ¹H NMR (400 MHz,CDCl₃) δ 7.49-7.37 (m, 2H), 7.38-7.30 (m, 3H), 7.21-7.13 (m, 4H),7.02-7.00 (d, J=9.4 Hz, 2H), 5.46-5.43 (t, J=5.2 Hz, 1H), 4.28 (d, J=53Hz, 2H), 3.70 (s, 3H), 3.63 (s, 2H). MS (ESI) m/z: 495.2 (MH+).

Step 3:2-(4-((3-(2,6-difluoro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl))ureido)methyl)phenyl)acetic acid

2-(4-((3-2,6-difluoro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methylacetate (7 mg, 0.014 mmol), sodium hydroxide (17 mg, 0.042 mmol),ethanol (1 mL), and water (0.3 mL) were added to a 100 mL single-mouthbottle, reacted for 2 hours at room temperature. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate (10mL×3). The organic layer was concentrated in vacuo to give the productof2-(4-((3-(2,6-difluoro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl))ureido)methyl)phenyl)aceticacid (white solid, 5 mg), with a yield of 73.5%. ¹H NMR (400 MHz, CD₃OD)δ 7.58-7.47 (m, 1H), 7.37 (m, 3H), 7.29 (q, J=10.6, 4H), 7.17 (d, J=9.9Hz, 2H), 4.39 (s, 2H), 3.59 (s, 2H). MS (ESI) m/z: 481.2 (MH+).

Example 202-(4-((3-(2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)aceticacid)

Step 1: 2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenylyl]-4-amine

4-bromo-3, 5-dichloroaniline (500 mg, 2.07 mmol),2-difluoromethoxybenzene borate (672 mg, 2.49 mmol), Pd₂(dba)₃ (378 mg,0.4 mmol), tri-tert-butylphosphonium tetrafluoroborate (180 mg, 0.62mmol), cesium carbonate (2.02 g, 6.01 mmol), and 1,4-dioxane/water (13mL/2 mL) were added to a microwave tube. The mixture was nitrogensparged for 5 min, stirred and heated to 120° C. for 3 hours undermicrowave, washed with saturated ammonium chloride (20 mL), andseparated by silica gel column (petroleum ether:ethyl acetate=10:1-5:1)to give the product of2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenylyl]-4-amine (yellow oil,140 mg), with a yield of 15.5%. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.40 (t,J=6.8 Hz, 1H), 7.31-7.27 (t, J=8 Hz, 1H), 7.25-7.20 (m, 2H), 6.72 (s,2H), 6.55-6.18 (t, J=74.1 Hz, 1H), 3.86 (s, 2H).

Step 22-(4-((3-(2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methylacetate

2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenylyl]-4-amine (50 mg, 0.11mmol), dichloromethane (2 mL) and DIEA (63 mg, 0.49 mmol) were added toa 25 mL single-mouth bottle, and stirred under ice bath for 5 minutes,and then triphosgene (19.5 mg, 0.066 mmol) was added, and the reactionwas continued under ice bath for 30 min, and then methyl4-aminomethylphenylacetate (35 mg, 0.197 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography(dichloromethane:methanol=50:1) to give the product of2-(4-((3-(2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methylacetate (yellow oil, 33 mg), with a yield of 49.3%. ¹H NMR (400 MHz,CDCl₃) δ 7.68 (s, 1H), 7.44-7.40 (t, J=7.8 Hz, 1H), 7.35 (s, 2H),7.30-7.26 (t, J=8.0 Hz, 1H), 7.24-7.21 (d, J=8.2 Hz, 1H), 7.20-7.08 (m,5H), 6.53-6.18 (t, J=74.0 Hz, 1H), 5.77 (d, J=5.1 Hz, 1H), 4.24-4.22 (d,J=5.3 Hz, 2H), 3.68 (s, 3H), 3.60 (s, 2H). MS (ESI) m/z: 509.1 (MIFF).

Step 32-(4-((3-(2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenylyl]-4-yl)ureido)methyl)phenyl)aceticacid

2-(4-((3-(2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methyl acetate (33 mg, 0.065 mmol), sodium hydroxide (7.78mg, 0.19 mmol), ethanol (2 mL), and water (0.5 mL) were added to a 25 mLsingle-mouth bottle, and reacted for 2 hours at room temperature. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethylacetate (10 mL×3). The organic layer was concentrated in vacuo to givethe product of2-(4-((3-(2,6-dichloro-2′-(difluoromethoxy)-[1,1′-biphenylyl]-4-yl)ureido)methyl)phenyl)acetic acid (white solid, 30 mg), with a yield of 90.9%. ¹H NMR(400 MHz, CD₃OD) δ 7.57 (s, 2H), 7.44 (t, J=7.2 Hz, 1H), 7.31-7.25 (m,5H), 7.24-7.20 (t, J=8.0 Hz, 2H), 6.85-6.8 (t, J=73.9 Hz, 1H), 4.38 (s,2H), 3.59 (s, 2H). MS (ESI) m/z: 495.1 (MH+).

Example 212-(4-((3-(2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)aceticacid

Step 1:2-(2-(difluoromethoxy)benzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

2-difluoromethoxybromobenzene (2 g, 9 mmol), bis(pinacolato)diboron (4.6g, 18 mmol), potassium acetate (3.62 g, 36 mmol), Pd(dppf)Cl₂ (73 mg,0.09 mmol), and 1,4-dioxane (100 mL) were added to a 100 mL three-neckedbottle, heated to 120° C. and reacted overnight while stirring. Themixture was cooled to room temperature, and added with water (50 mL),and extracted with ethyl acetate (50 mL×3). The organic layers werecombined, washed with saturated sodium chloride (100 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by a silica gel column (petroleum ether:ethyl acetate=50:1) togive the product of 2-(2-(difluoromethoxy)benzyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (orange solid, 2.1 g),with a yield of 86.7%. ¹H NMR (400 MHz, CDCl₃) δ 7.76-7.75 (d, J=6.3 Hz,1H), 7.43 (t, J=6.9 Hz, 1H), 7.26-7.22 (d, J=7.2 Hz, 1H), 7.15 (d, J=8.2Hz, 1H), 6.52 (t, J=75.5 Hz, 1H), 1.35 (s, 12H).

Step 2: 4-bromo-3, 5-dimethylaniline

3,5-dimethylaniline (2 g, 16.5 mmol), and acetonitrile (80 mL) wereadded to a 25 mL single-mouth bottle, and stirred for 5 min under icebath, then NBS (3.94 g, 21.6 mmol) was dissolved in acetonitrile (20mL)), added dropwise to the single-mouth bottle, and after addition,reacted for 2 hours under ice bath. After the reaction, water (50 mL)was added, and the mixture was extracted with ethyl acetate (100 mL×3).The organic layers were combined, and concentrated in vacuo to removethe solvent to separate by a silica gel column (petroleum ether:ethylacetate=10:1-4:1) to give the product of 4-bromo-3, 5-dimethylaniline(white solid, 2.3 g), with a yield of 69.7%. ¹H NMR (400 MHz, CDCl₃) δ6.44 (s, 2H), 3.45 (s, 2H), 2.31 (s, 6H). MS (ESI) m/z: 200.1 (MH+).

Step 3: 2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-dibiphenylyl]-4-amine

4-bromo-3,5-dimethylaniline (293 mg, 1.46 mmol),2-difluoromethoxybenzene borate (330 mg, 1.2 mmol), Pd₂(dba)₃ (110 mg,0.12 mmol), tert-butylphosphonium tetrafluoroborate (104 mg, 0.36 mmol),cesium carbonate (1.17 g, 3.6 mmol) and 1,4-dioxane/water (4 mL/1 mL)were added to a microwave tube. The mixture was nitrogen sparged for 5min, and stirred and heated to 120° C. for 3 hours under microwave. Themixture then was washed with saturated ammonium chloride (20 mL), andseparated by silica gel column (petroleum ether:ethyl acetate=10:1-4:1)to give the product of2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-dibiphenylyl]-4-amine (yellowoil, 62 mg), with a yield of 15.6%. ¹H NMR (400 MHz, CDCl₃) δ 7.3,7-7.33 (t, J=1.6, 1H), 7.30-7.21 (m, 2H), 7.17 (dd, 7=7.3, 1.1 Hz, 1H),6.48 (s, 2H), 6.45-6.07 (t, J=74.6 Hz, 1H), 3.50 (s, 2H), 1.95 (s, 6H).MS (ESI) m/z: 264.1 (MH+).

Step 4:2-(4-((3-(2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methyl acetate

2,6-dimethyl-2′-(difluoromethoxy)-[1,1′-biphenylyl]-4-amine (30 mg, 0.11mmol), DCM (2 mL), and DIEA (28 mg, 0.22 mmol) were added to a 25 mLsingle-mouth bottle, and stirred for 5 min under ice bath, and thentriphosgene (13 mg, 0.044 mmol) was added, and the reaction wascontinued under ice bath for 30 min, and then methyl4-aminomethylphenylacetate (25 mg, 0.14 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography(dichloromethane:methanol=20:1) to give the product of2-(4-((3-(2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methyl acetate (yellow oil, 43 mg), with a yield of 81.1%. ¹H NMR (400MHz, CDCl₃) δ 7.37-7.35 (t, J=7.6 Hz, 1H), 7.27-7.19 (m, 7H), 7.10-7.08(d, J=7.3 Hz, 1H), 7.01 (s, 1H), 6.44-6.07 (t, J=74.2 Hz, 1H), 5.55 (d,J=5.4 Hz, 1H), 4.37-4.35 (d, J=5.4 Hz, 2H), 3.68 (s, 3H), 3.61 (s, 2H),1.94 (s, 6H). MS (ESI) m/z: 469.2 (MH+).

Step 5:2-(4-((3-(2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid

2-(4-((3-(2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (43 mg, 0.092 mmol), sodium hydroxide (11 mg, 0.28 mmol),ethanol (3 mL) and water (1 mL) were added to a 25 mL single-mouthbottle to react for 1 hour at room temperature. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate (10mL×3). The organic layer was concentrated in vacuo to give the productof2-(4-((3-(2′-(difluoromethoxy)-2,6-dimethyl-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid (white solid, 36 mg), with a yield of 84.0%. ¹H NMR (400MHz, CD₃OD) δ 7.42-7.39 (t, J=7.0 Hz, 1H), 7.34-7.23 (m, 6H), 7.13-7.12(m, 3H), 6.79-6.42 (t, J=74.4 Hz, 2H), 4.38 (s, 2H), 3.59 (s, 2H), 1.95(s, 6H). MS (ESI) m/z: 455.2 (MH+).

Example 222-(4-((3-(2-(1-methyl-1H-pyrazol-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid and

2-(4-((3-(2′-(1-methyl-1H-pyrazol-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid

Step 1: 1-bromo-2-chloro-4 nitrobenzene

2-chloro-4-nitroaniline (5 g, 28.9 mmol), copper bromide (7.73 g, 34.7mmol), and acetonitrile (80 mL) were added to a 25 mL single-mouthbottle, and stirred for 5 minutes under ice bath, and n-pentyl nitrite(6.76 g, 57.8 mmol) was weighed and added to acetonitrile (20 mL). Andthen the obtained mixture was added dropwise to the reaction solutionunder ice bath, and then reacted for 30 minutes under ice bath. Thereaction mixture was naturally warmed to room temperature and allowed toreact overnight. Water (100 mL) was added, and the mixture was extractedwith ethyl acetate (100 mL×3), washed with water (100 mL), washed withsaturated sodium chloride (100 mL), dried over anhydrous sodium sulfate,and concentrated in vacuo to give the product of 1-bromo-2-chloro-4nitrobenzene (yellow solid, 5.68 g), with a yield of 82.9%.

Step 2: 2-chloro-4-nitro-2′-trifluoromethoxy-1,1′-biphenyl

1-bromo-2-chloro-4-nitrobenzene (1 g, 0.42 mmol),2-trifluoromethoxybenzeneboronic acid (1.05 g, 0.51 mmol), Pd₂(dppf)Cl₂(160 mg, 0.02 mmol), cesium carbonate (2.77 g, 1.26 mmol), and CH₃CN/H₂O(12 mL/3 mL) were added to a microwave tube. The mixture was nitrogensparged for 5 minutes, and stirred and heated to 100° C. for 2 hoursunder microwave. Ethyl acetate (20 mL) was added, and the mixture waswashed with saturated ammonium chloride (20 mL), and the solvent wasdried with rotation under vacuum. The crude product was separated bysilica gel column (petroleum ether:ethyl acetate=30:1) to give theproduct of 2-chloro-4-nitro-2′-trifluoromethoxy-1,1′-biphenyl (yellowoil, 1.47 g), with a yield of 99.3%. ¹H NMR (400 MHz, CDCl₃) δ 8.38-8.37(d, J=2.1 Hz, 1H), 8.21-8.18 (dd, J=8.4, 2.2 Hz, 1H), 7.56-7.47 (m, 2H),7.45-7.39 (m, 2H), 7.37-7.30 (m, 1H).

Step 3:4,4,5,5-tetramethyl-2-(4-nitro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-1,3,2-dioxaborolan

2-chloro-4-nitro-2′-(trifluoromethoxy)-1,1′-biphenyl (500 mg, 1.55mmol), bis(pinacolato)diboron (800 mg, 4.65 mmol), Pd₂(dba)₃ (115 mg,0.13 mmol), potassium acetate (465 mg, 4.65 mmol), x-phos (240 mg, 0.5mmol) and 1,4-dioxane (15 mL) were added to a microwave tube. Themixture was nitrogen sparged for 5 min, and stirred and heated to 90° C.for 2 hours under microwave. Then ethyl acetate (20 mL) was added, andthe mixture was washed with saturated ammonium chloride (20 mL), and thesolvent was dried with rotation under vacuum, and the crude product wasseparated by silica gel column (petroleum ether:ethyl acetate=6:1) togive the product of4,4,5,5-tetramethyl-2-(4-nitro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-1,3,2-dioxaborolan(yellow oil, 130 mg), with a yield of 20.2%.

Step 4:1-methyl-4-(4-nitro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-1H-pyrazoleand

1-methyl-4-(4′-nitro-6-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-1H-pyrazole4,4,5,5-tetramethyl-2-(4-nitro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-1,3,2-dioxaborolan(100 mg, 0.2 mmol), 4-bromo-1-methyl-1H-pyrazole (47 mg, 0.29 mmol),tetrakis(triphenylphosphine)palladium (22 mg, 0.014 mmol), sodiumcarbonate (80 mg, 0.75 mmol), and 1,4-dioxane/H₂O (4 mL/1 mL) were addedto a microwave tube. The mixture was nitrogen sparged for 5 min, andstirred and heated to 90° C. for 1.5 hours under microwave, and theresulting mixture was washed with saturated ammonium chloride (20 mL),and separated by silica gel column (petroleum ether:ethyl acetate=1:1)to give the two bathes of yellow oils (15 mg and 20 mg respectively).

Step 5:2-(1-methyl-1H-pyrazole-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amineand2′-(1-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine

1-methyl-4-(4-nitro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-1H-pyrazole(15 mg, 0.04 mmol), stannous chloride monohydrate (37 mg, 0.16 mmol),ethanol (2 mL), and concentrated hydrochloric acid (0.25 mL) were addedto a 25 mL single-mouth bottle, and heated at 70° C. to react for threehours. After confirming completion of the reaction by TLC, the mixturewas cooled to room temperature, added with 2N solution of hydrogenchloride (10 mL), and extracted with ethyl acetate (20 mL×3). Theorganic layers were combined, and washed with saturated sodium chloride(30 mL), and the solvent was dried with rotation under vacuum was togive the product of2-(1-methyl-1H-pyrazole-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine(white solid, 12.5 mg).

1-methyl-4-(4′-nitro-6-(trifluoromethoxy)-[1,1′-biphenyl]-2-yl)-1H-pyrazole(20 mg, 0.05 mmol), stannous chloride monohydrate (37 mg, 0.16 mmol),ethanol (2 mL), and concentrated hydrochloric acid (0.25 mL) were addedto a 25 mL single-mouth bottle, and heated at 70° C. to react for threehours. After confirming completion of the reaction by TLC, the mixturewas cooled to room temperature, added with 2N solution of hydrogenchloride (10 mL), and extracted with ethyl acetate (20 mL×3). Theorganic layers were combined, and washed with saturated sodium chloride(30 mL), and the solvent was dried with rotation under vacuum to givethe product of2′41-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine(white solid, 16 mg).

Step 62-(4-((3-(2-(1-methyl-1H-pyrazole-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate and2-(4-((3-(2′-(1-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methyl acetate

2-(1-methyl-1H-pyrazole-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine(12.5 mg, 0.037 mmol), DCM (2 mL), and DIEA (9.5 mg, 0.074 mmol) wereadded to a 25 mL single-mouth bottle, and stirred for 5 min under icebath, and then triphosgene (4.4 mg, 0.015 mmol) was added, and thereaction was continued under ice bath for 30 min, and then methyl4-aminomethylphenylacetate (7.39 mg, 0.04 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=1:1) to give the product of2-(4-((3-(2-(1-methyl-1H-pyrazole-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methyl acetate (white solid, 12 mg), with a yield of60.0%. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.39-7.28 (m, 2H),7.25-7.16 (m, 7H), 7.17-7.09 (m, 2H), 7.04 (s, 1H), 6.89 (s, 1H), 5.64(s, 1H), 4.33 (s, 2H), 3.67 (s, 3H), 3.66 (s, 3H), 3.58 (s, 2H). MS(ESI) m/z: 539.2 (MI-1+).

2′-(1-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-phenyl]-4-amine(16 mg, 0.048 mmol), DCM (2 mL), and DIEA (13 mg, 0.096 mmol) were addedto a 25 mL single-mouth bottle, and stirred for 5 min under ice bath,and then triphosgene (5.7 mg, 0.019 mmol) was added, and the reactionwas continued under ice bath for 30 min, and then methyl4-aminomethylphenylacetate (9.46 mg, 0.053 mmol) was added, and thereaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=1:1) to give the product of2-(4-((3-(2′-(1-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methyl acetate (yellow solid, 10 mg), with a yield of38.7%. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.28 (m, 4H), 7.25-7.12 (m, 6H),7.11-7.01 (m, 3H), 6.78 (s, 1H), 5.47 (s, 1H), 4.38 (s, 2H), 3.69 (s,3H), 3.68 (s, 3H) 3.61 (s, 2H). MS (ESI) m/z: 539.2 (MIFF).

Step 72-(4-((3-(2-(1-methyl-1H-pyrazol-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl))ureido)methyl)benzyl)aceticacid and2-(4-((3-(2′-(1-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)aceticacid

2-(4-((3-(2-(1-methyl-1H-pyrazole-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (12 mg, 0.022 mmol), sodium hydroxide (1.92 mg, 0.04 mmol),ethanol (1 mL), and water (0.3 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate (10mL×3), and the organic layer was concentrated in vacuo to give theproduct of2-(4-((3-(2-(1-methyl-1H-pyrazol-4-yl)-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl))ureido)methyl)benzyl)aceticacid (white solid, 10 mg), with a yield of 85.6%. ¹H NMR (400 MHz,CD₃OD) δ 7.61-7.60 (d, J=2.0 Hz, 1H), 7.43-7.42 (d, J=6.1 Hz, 1H),7.39-7.33 (m, 1H), 7.32-7.25 (m, 6H), 7.23-7.22 (d, J=4.7 Hz, 2H),7.15-7.13 (d, J=8.4 Hz, 1H), 6.97 (s, 1H), 4.40 (s, 2H), 3.75 (s, 3H),3.59 (s, 2H). MS (ESI) m/z: 525.2 (MH+).

2-(4-((3-(2′-(1-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)methylacetate (10 mg, 0.018 mmol), sodium hydroxide (1.92 mg, 0.04 mmol),ethanol (1 mL), and water (0.3 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate (10mL×3). The organic layer was concentrated in vacuo to give the productof2-(4-((3-(2′-(1-methyl-1H-pyrazole-4-yl)-6′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)benzyl)aceticacid (white solid, 5 mg), with a yield of 51.2%. ¹H NMR (400 MHz, CD₃OD)δ 7.61 (d, J=1.9 Hz, 1H), 7.45-7.42 (t, J=10.9, 4.6 Hz, 1H), 7.37-7.33(t, J=7.5 Hz, 1H), 7.32-7.25 (m, 7H), 7.22 (s, 1H), 7.15-7.14 (d, J=8.3Hz, 1H), 6.97 (s, 1H), 4.39 (s, 2H), 3.73 (s, 3H), 3.57 (s, 2H). MS(ESI) m/z: 525.2 (MH+).

Example 23: 2-(4-((3-([1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)aceticacid

Step 1: methyl 4-aminomethylphenylacetate

P-methyl cyanobenzoate (200 mg, 1.14 mmol), methanol (2 mL), a smallamount of Pd/C, and 2 drops of concentrated hydrochloric acid were addedto a 25 mL single-mouth bottle under an hydrogen atmosphere at anatmospheric pressure; and stirred to react at room temperature for threehours. After confirming completion of the reaction by TLC, the mixturewas filtered and concentrated in vacuo to give the product of methyl4-aminomethylphenylacetate (white solid, 178 mg), with a yield of 74.2%.¹H NMR (400 MHz, DMSO) δ 8.22 (s, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.30 (d,J=8.1 Hz, 2H), 3.98 (s, 2H), 3.71 (s, 2H), 3.61 (s, 3H). MS (ESI) m/z:180.1 (MI-1+).

Step 2: 2-(4-((3([1,1′-biphenylyl-4-yl]ureido)methyl)benzyl)methylacetate

4-(aminomethyl) methyl phenylacetate (76 mg, 0.45 mmol), dichloromethane(2 mL), and DIEA (116 mg, 0.90 mmol) were added to a 25 mL single-mouthbottle, and stirred for 5 min under ice bath, and then triphosgene (44mg, 0.15 mmol) was added, and the reaction was continued under ice bathfor 30 min, and then 4-biphenylamine (80 mg, 0.45 mmol) was added, andthe reaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=1:1) to give the product of2-(4-((3([1,1′-biphenylyl-4-yl]ureido)methyl)benzyl)methyl acetate(white solid, 60 mg), with a yield of 37.9%. ¹H NMR (400 MHz, CDCl₃) δ7.55-7.50 (m, 3H), 7.45-7.39 (m, 2H), 7.37-7.30 (m, 2H), 7.27-7.25 (m,2H), 7.22-7.20 (m, 3H), 4.40 (s, 2H), 3.68 (s, 3H), 3.61-3.60 (d, J=2.6Hz, 2H). MS (ESI) m/z: 374.9 (MH+).

Step 3: 2-(4-((3([1,1′-biphenylyl-4-yl]ureido)methyl)benzyl)acetic acid

2-(4-((3([1,1′-biphenylyl-4-yl]ureido)methyl)benzyl)methyl acetate (60mg, 0.16 mmol), sodium hydroxide (19 mg 0.48 mmol), ethanol (2 mL), andH₂O (1 mL) were added to a 25 mL single-mouth bottle, and reacted atroom temperature for 2 hours. After confirming completion of thereaction of materials by TLC, the mixture was adjusted to pH 3 with 2Nhydrochloric acid, and extracted with ethyl acetate (10 mL×3), and theorganic layer was concentrated in vacuo to give the product of2-(4-((3([1,1′-biphenylyl-4-yl]ureido)methyl)benzyl)acetic acid (whitesolid, 40 mg), with a yield of 87.7%. ¹H NMR (400 MHz, DMSO) δ 8.68 (s,1H), 7.60-7.58 (d, J=7.2 Hz, 2H), 7.54-7.52 (d, J=8.8 Hz, 2H), 7.49-7.47(d, J=8.8 Hz, 2H), 7.42-7.48 (t, J=7.7 Hz, 2H), 7.29-7.27 (t, J=7.3 Hz,1H), 7.25-7.21 (q, J=6.3 Hz, 3H), 7.17 (s, 1H), 6.64 (s, 1H), 4.27 (d,J=5.8 Hz, 2H), 4.18 (d, J=4.8 Hz, 1H), 3.52 (s, 2H). MS (ESI) m/z: 361.0(MIFF).

Example 242-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)propanoicacid

Step 1: methyl 2-(4-cyanobenzyl) isopropanoate

Methyl p-cyanophenylacetate (300 mg, 0.86 mmol), and tetrahydrofuran (2mL) were added to a 25 mL single-mouth bottle, and stirred for 10 minunder ice bath, then NaH (81 mg, 1.02 mmol, 60%) was added, and thereaction was continued under ice bath for 10 min. Then iodomethane (243mg, 0.86 mmol) was added, and the reaction was continued for 1 hourwhile stirring, and after completion of the reaction, the reaction wasquenched with water. The reaction mixture was adjusted to pH 3 with 2Mhydrochloric acid solution, and extracted with ethyl acetate (10 mL×3).The organic layers were combined, washed with saturated brine, driedover anhydrous sodium sulfate, and filtered, and then the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product waspassed through a column (ethyl acetate:petroleum ether=1:1) to give theproduct (white oil, 190 mg), with a yield of 58.6%. ¹H NMR (400 MHz,CDCl₃) δ 7.62 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 3.78 (q, J=7.1Hz, 1H), 3.67 (s, 3H), 1.51 (d, J=7.2 Hz, 3H). MS (ES) m/z: 190.0 (MH⁺).

Step 2: 2-(4-aminomethylbenzyl)methyl isopropylate

2-(4-cyanobenzyl)propanoate methyl ester (190 mg, 1.0 mmol), methanol(10 mL), tetrahydrofuran (2 mL), aqueous ammonia (0.5 mL, 28%) and RaneyNi (100 mg) were added to a 25 mL single-mouth bottle, and the reactionmixture was stirred at room temperature for 30 min, and filtered overcelite, and the solvent was dried with rotation under vacuum to give theanhydrous solid product (140 mg), with a yield of 72.9%. MS (ES) m/z:194.1 (MH+).

Step 3:2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methylisopropylate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), DCM (4 mL), and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, and stirred under ice bath for 10 min, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 30 min, and then 2-(4-aminomethylbenzyl)methylisopropylate (71 mg, 0.37 mmol) was added, and the reaction wascontinued under ice bath for 30 min, then at room temperature overnight.H₂O (10 mL) was added, and the mixture was extracted withdichloromethane (10 mL×3). The organic layers were combined, washed withsaturated sodium chloride (10 mL), dried over anhydrous sodium sulfate,and filtered, and the filtrate was concentrated in vacuo to obtain acrude product. The crude product was separated by preparative thin layerchromatography (dichloromethane:methanol=20:1) to give the product(white solid, 65 mg), with a yield of 38.7%. ¹H NMR (400 MHz, CDCl₃) δ7.99 (d, J=5.7 Hz, 1H), 7.48-7.41 (m, 1H), 7.41 (s, 2H), 7.33 (t, J=7.6Hz, 2H), 7.21-7.10 (m, 5H), 6.11-6.01 (m, 1H), 4.26 (d, J=5.6 Hz, 2H),3.69 (d, J=7.2 Hz, 1H), 3.61 (s, 3H), 1.44 (d, J=7.2 Hz, 3H). MS (ES)m/z: 540.7 (MH⁺).

Step 4:2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl) isopropyl acid

2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methyl isopropylate (65 mg, 0.12 mmol), lithium hydroxidemonohydrate (15 mg, 0.36 mmol), ethanol (2 mL), tetrahydrofuran (2 mL),and water (0.3 mL) were added to a 25 mL single-mouth bottle, andreacted at room temperature for 2 hours. After confirming completion ofthe reaction of materials by TLC, the mixture was adjusted to pH 3 with2N hydrochloric acid, and extracted with ethyl acetate (10 mL×3). Theorganic layer was concentrated in vacuo to give the product (whitesolid, 35 mg), with a yield of 56.4%. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (s,2H), 7.50 (td, J=8.1, 1.4 Hz, 1H), 7.43-7.35 (m, 2H), 7.31-7.23 (m, 5H),4.37 (s, 2H), 3.69 (q, J=7.1 Hz, 1H), 1.43 (d, J=7.1 Hz, 3H). MS (ES)m/z: 526.8 (MH⁺).

Example 25: 2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2,2-difluoroaceticacid

Step 1: 2-(4-cyanobenzyl)-2,2-ethyl difluoroacetate

4-iodobenzonitrile (940 mg, 4.21 mmol), DMSO (10 mL), 2-bromo-2,2-ethyldifluoroacetate (940 mg, 4.63 mmol), and copper powder (539 mg) wereadded to a 25 mL single-mouth bottle, heated to react at 65° C. for 18hours, and cooled to room temperature. Then water (40 mL) was added, andthe mixture was extracted with ethyl acetate (20 mL×3). The organiclayers were combined, concentrated in vacuo and separated by a silicagel column (petroleum ether:acetic acid ester=200:1) to give the productof 2-(4-cyanobenzyl)-2,2-ethyl difluoroacetate (anhydrous liquid, 670mg), with a yield of 70.8%. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (q, J=8.5 Hz,4H), 4.31 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H).

Step 2: 2-(4-(aminomethyl)phenyl)-2,2-ethyl difluoroacetate

A small amount of Raney Ni, 2-(4-cyanobenzyl)-2,2-ethyl difluoroacetate(200 mg), absolute ethanol (4 mL), and a solution of hydrochloric acidin diethyl ether (0.5 mL) were added to a 25 mL single-mouth bottle. Thehydrogen gas was introduced to enable the mixture to react at roomtemperature for 10 minutes. After confirming completion of the reactionof materials by TLC, the mixture was filtered by celite and concentratedin vacuo, and the crude product was separated by a columndichloromethane:methanol=10:1) to give the product of2-(4-(aminomethyl)phenyl)-2,2-ethyl difluoroacetate (orange solid, 100mg), with a yield of 49.2%. MS (ESI) m/z: 230.1 (MH+).

Step 32-(4-((3-(2,6-chloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2,2-ethyldifluoroacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), DCM (4 mL), and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, and stirred under ice bath for 10 min, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedfor 30 minutes under ice bath, and then2-(4-(aminomethyl)phenyl)-2,2-ethyl difluoroacetate (85 mg, 0.37 mmol)was dissolved in DMF (1 mL) and added, and the reaction was continuedunder ice bath for 30 min. H₂O (10 mL) was added, and the mixture waswashed with saturated ammonium chloride, extracted with dichloromethane(10 mL×3). The organic layers were combined, washed with saturatedsodium chloride (10 mL), dried over anhydrous sodium sulfate, andfiltered, and the filtrate was concentrated in vacuo to obtain a crudeproduct. The crude product was separated by preparative thin layerchromatography (dichloromethane:methanol=20:1) to give the product(white solid, 30 mg), with a yield of 16.8%. H¹ NMR (400 MHz, CDCl₃) δ7.82 (s, 1H), 7.50 (d, J=7.9 Hz, 2H), 7.46 (s, 2H), 7.45-7.40 (m, 1H),7.36-7.28 (m, 5H), 7.20 (d, J=7.0 Hz, 1H), 6.09 (s, 1H), 4.38 (d, J=5.1Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 1.29-1.25 (m, 4H). MS (ESI) m/z: 574.7(M−1).

Step 42-(4-((3-(2,6-chloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2,2-difluoroaceticacid

2-(4-((3-(2,6-chloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2,2-ethyldifluoroacetate (30 mg, 0.035 mmol), lithium hydroxide (4.27 mg, 0.1mmol), ethanol (2 mL), and water (0.5 mL) were added to a 25 mLsingle-mouth bottle, and reacted at room temperature for 2 hours. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethylacetate (10 mL×3). The organic layer was concentrated in vacuo to givethe product of2-(4-((3-(2,6-chloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2,2-difluoroaceticacid (white solid, 25 mg), with a yield of 71.4%. ¹H NMR (400 MHz,CD₃OD) δ 7.62-7.55 (m, 4H), 7.55-7.49 (m, 1H), 7.49-7.43 (m, 3H), 7.40(t, J=7.6 Hz, 2H), 7.30 (t, J=10.1 Hz, 1H), 4.46 (s, 2H). MS (ESI) m/z:548.8 (MH+).

Example 262-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenoxy)aceticacid

Step 1: 2-(4-cyanophenoxyl)methyl acetate

4-cyanophenol (1.32 g, 11 mmol), 2-methyl bromoacetate (2 g, 13 mmol),potassium carbonate (4.15 g, 33 mmol), and acetonitrile (25 mL) wereadded to a 50 mL single-mouth bottle one by one, and heated to react at70° C. for 1.5 hours. After completion of the reaction, the reactionmixture was cooled, and filtered, and the solvent was dried withrotation under vacuum to give the product of 2-(4-cyanophenoxyl)methylacetate (white solid, 2.28 g), with a yield of 100%. H¹ NMR (400 MHz,CDCl₃) δ 7.62-7.60 (d, J=8.9 Hz, 2H), 6.97-6.96 (d, J=8.9 Hz, 2H), 4.69(s, 2H), 3.82 (s, 3H).

Step 2: 2-(4-(aminomethyl)phenoxyl)methyl acetate

2-(4-cyanophenoxyl)methyl acetate (500 mg, 2.62 mmol), methanol (10 mL),and concentrated hydrochloric acid (1 mL) were added to a 25 mLsingle-mouth bottle, and then Pd/C (50 mg) was added. The obtainedmixture reacted for two hours at room temperature under hydrogenenvironment at an atmospheric pressure, and filtered over celite, andthen the filtrate was concentrated in vacuo to give the product of2-(4-(aminomethyl)phenoxyl)methyl acetate (yellow solid, 560 mg), with ayield of 92.7%. H¹ NMR (400 MHz, DMSO) δ 8.28 (s, 3H), 7.42-7.40 (d,J=8.5 Hz, 2H), 6.98-6.96 (d, J=8.6 Hz, 2H), 4.83 (s, 2H), 3.94 (s, 2H),3.69 (s, 3H).

Step 32-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenoxyl)ethylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (60 mg, 0.1mmol), DCM (4 mL), and DIEA (72 mg, 0.56 mmol) were added to a 25 mLsingle-mouth bottle, and stirred under ice bath for 5 minutes, and thentriphosgene (22 mg, 0.074 mmol) was added, and the reaction wascontinued under ice bath for 30 min, and then2-(4-(aminomethyl)phenoxyl)methyl acetate (44 mg, 0.20 mmol) was added,and the reaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture wasextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (developing solventpetroleum ether:ethyl acetate=1:1) to give the product of2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenoxyl)ethylacetate (white solid, 38 mg), with a yield of 37.6%. ¹H NMR (400 MHz,CDCl₃) δ 7.76 (s, 1H), 7.49-7.37 (m, 3H), 7.38-7.30 (m, 2H), 7.21-7.19(d, J=6.6 Hz, 1H), 7.10-7.07 (d, J=8.4 Hz, 2H), 6.75-6.73 (d, J=8.5 Hz,2H), 5.89 (s, 1H), 4.58 (s, 2H), 4.22 (d, J=3.6 Hz, 2H), 3.78 (s, 3H).MS (ESI) m/z: 541.0 (M−1).

Step 4:2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenoxyl)acetic acid

2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenoxyl)ethylacetate (38 mg, 0.07 mmol), lithium hydroxide (8.8 mg, 0.21 mmol),ethanol (1 mL), and water (0.3 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and extracted with ethyl acetate (10mL×3), and the organic layer was concentrated in vacuo to give theproduct of2-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenoxyl)acetic acid (white solid, 34 mg), with a yield of 91.2%.¹H NMR (400 MHz, CD₃OD) δ 7.58 (s, 2H), 7.52 (t, J=7.1 Hz, 1H), 7.41(dd, J=15.3, 7.8 Hz, 2H), 7.28 (t, J=7.1 Hz, 3H), 6.95-6.87 (m, 2H),4.67 (d, J=22.3 Hz, 2H), 4.33 (s, 2H), 3.77 (s, 1H). MS (ESI) m/z: 529.0(M−1).

Example 272-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-3-methylureido)methyl)phenyl)acetic acid

Step 1:2,6-dichloro-N-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-amine

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), tetrahydrofuran (1 mL), paraformaldehyde (17 mg, 0.45 mmol)and acetic acid (2 drops) were added to a 25 mL single-mouth bottle, andstirred at room temperature for 2 h, and then sodium cyanoborohydride(30 mg, 0.9 mmol) was added, and the reaction was continued at roomtemperature overnight. After completion of reaction, H₂O (20 mL) wasadded, and the mixture was extracted with ethyl acetate (20 mL×3). Theorganic layers were combined, and washed with saturated sodium chloride(30 mL), and the solvent was dried with rotation under vacuum, and thecrude product was passed through a silica gel column (petroleumether:ethyl acetate=20:1) to give the product of2,6-dichloro-N-methyl-T-(trifluoromethoxy)-[1,1′-biphenyl]-4-amine(white oil, 45 mg), with a yield of 26.9%. ¹H NMR (400 MHz, CDCl₃) δ7.47-7.40 (m, 1H), 7.39-7.32 (m, 2H), 7.31-7.27 (m, 1H), 6.63 (s, 2H),2.85 (s, 3H). MS (ESI) m/z: 336.0 (MH+).

Step 22-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methylureido)methyl)phenyl)methylacetate

2,6-dichloro-N-methyl-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-amine (45mg, 0.14 mmol), dichloromethane (4 mL), and DIEA (54 mg, 0.42 mmol) wereadded to a 25 mL single-mouth bottle, and stirred for 5 min under icebath, and then triphosgene (16 mg, 0.05 mmol) was added, and thereaction was continued under ice bath for 30 min, and thendichloromethane (10 mL) was added. The mixture was washed with saturatedammonium chloride (10 mL), the solvent was dried with rotation undervacuum in the organic layer, and the obtained product was vacuum dried.The resulting product was dissolved in tetrahydrofuran (2 mL), thenmethyl 4-aminomethylphenylacetate (30 mg, 0.14 mmol), and DIEA (54 mg,0.28 mmol) were added to react at 60° C. overnight. The obtained mixturewas concentrated in vacuo to remove the solvent, and the crude productwas separated by preparative thin layer chromatography (petroleumether:ethyl acetate=2:1) to give the product of2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methylureido)methyl)phenyl)methylacetate (white solid, 52 mg), with a yield of 72.2%. MS (ESI) m/z: 541.1(MH+).

Step 32-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methylureido)methyl)phenyl)aceticacid

2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-3-methylureido)methyl)phenyl)methyl acetate (50 mg, 0.09 mmol), sodium hydroxide (11mg, 0.27 mmol), ethanol (1 mL), and water (0.3 mL) were added to a 25 mLsingle-mouth bottle, and reacted for 2 hours at room temperature. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethylacetate (10 mL×3). The organic layer was concentrated in vacuo to givethe product (white solid, 42 mg), with a yield of 86.2%. ¹H NMR (400MHz, CD₃OD) δ 7.55 (t, J=7.1 Hz, 1H), 7.48 (s, 2H), 7.44 (t, J=7.6 Hz,2H), 7.33-7.21 (m, 5H), 4.36 (s, 2H), 3.57 (s, 2H), 3.31 (s, 3H). MS(ESI) m/z: 526.7 (MIFF).

Example 282-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-1-methylureido)methyl)phenyl)acetic acid

Step 1: 2-(4-(bromomethyl)benzyl)acetic acid

p-methylphenylacetic acid (3.88 g, 25.9 mmol), NBS (4.83 g, 27.2 mmol),AIBN (42 mg, 0.26 mmol), and carbon tetrachloride (50 mL) were added toa 100 mL single-mouth bottle, and reacted at 90° C. for 4 hours. Themixture was concentrated in vacuo to remove the solvent under a reducedpressure, and was passed through a column (ethyl acetate:petroleumether=1:4) to give the product (white solid, 2.28 g), with a yield of40.8%. ¹H NMR (400 MHz, DMSO) δ 12.31 (s, 1H), 7.25 (d, J=7.6 Hz, 2H),7.11 (d, J=7.5 Hz, 2H), 4.56 (s, 2H), 3.44 (s, 2H). MS (ESI) m/z: 228.9(MH+)

Step 2: 2-(4-((methylamino)methyl)phenyl)acetic acid

A solution of methylamine in ethanol (0.5 mL) was added to a 25 mLsingle-mouth bottle. Then 2-(4-(bromomethyl)phenyl)acetic acid (1 g, 4.4mmol) was weighed and dissolved in dichloromethane (4 mL), and addeddropwise to the reaction mixture at room temperature. And afteraddition, the reaction was continued at room temperature for 1 hour, andreaction mixture was concentrated in vacuo to remove the solvent, andthe product was used in the next reaction directly. MS (ESI+) m/z: 180.1((MH+).

Step 3: 2-(4-((methylamino)methyl)benzyl)ethyl acetate

The 2-(4-((methylamino)methyl)benzyl)acetic acid obtained in step 2 wasdissolved in methanol (5 mL), then added with thionyl chloride (0.5 mL)and the obtained mixture was allowed to react at room temperature forhalf an hour. The reaction mixture was concentrated in vacuo to removethe solvent. Then water (20 mL) was added, and the mixture was adjustedto pH 8 with saturated sodium carbonate, extracted with ethyl acetate(20 mL×3), and dried over anhydrous sodium sulfate, and the organiclayer was concentrated in vacuo and passed through a silica gel column(petroleum ether:ethyl acetate=10:1-4:1) to give the product (whitesolid, 120 mg). (ESI+) m/z: 194.1 ((MIFF).

Step 4:2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1-methylureido)methyl)phenyl)ethylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (5 mL), and DIEA (120 mg, 0.93 mmol) wereadded to a 25 mL single-mouth bottle, and stirred under ice bath for 10min, and then triphosgene (35 mg, 0.11 mmol) was added, and the reactionwas continued under ice bath for 30 min, and then2-(4-((methylamino)methyl)phenyl)ethyl acetate (72 mg, 0.37 mmol) wasadded, and the reaction was continued under ice bath for 30 min, then atroom temperature overnight. H₂O (10 mL) was added, and the mixture waswashed with saturated ammonium chloride, extracted with dichloromethane(10 mL×3). The organic layers were combined, washed with saturatedsodium chloride (10 mL), dried over anhydrous sodium sulfate, andfiltered, and the filtrate was concentrated in vacuo to obtain a crudeproduct. The crude product was separated by preparative thin layerchromatography (dichloromethane:methanol=20:1) to give the product(white solid, 70 mg), with a yield of 41.9%. ¹H NMR (400 MHz, CDCl₃) δ7.51 (s, 2H), 7.48-7.42 (m, 1H), 7.36 (t, J=7.0 Hz, 2H), 7.33-7.28 (m,2H), 7.28-7.26 (m, 3H), 6.43 (s, 1H), 4.58 (s, 2H), 3.70 (s, 3H), 3.64(s, 2H), 3.05 (s, 3H). (ESI+) m/z: 540.7 ((MH+).

Step 52-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1-methylureido)methyl)phenyl)aceticacid

2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1-methylureido)methyl)phenyl)ethyl acetate (73 mg, 0.13 mmol), sodium hydroxide (16 mg,0.39 mmol), ethanol (2 mL), tetrahydrofuran (1 mL), and water (0.3 mL)were added to a 25 mL single-mouth bottle, and reacted at roomtemperature for 2 hours. The ethanol was spun off under an increasedpressure, water (5 mL) was added, and the mixture was adjusted to pH 3with 2N hydrochloric acid, and extracted with ethyl acetate (10 mL×3).The organic layer was concentrated in vacuo to give the product (whitesolid, 45 mg), with a yield of 61.6%. ¹H NMR (400 MHz, CD₃OD) δ 7.63 (s,2H), 7.48 (t, J=7.8 Hz, 1H), 7.42-7.32 (m, 2H), 7.29-7.18 (m, 5H), 4.56(s, 2H), 3.56 (s, 2H), 2.94 (s, 3H). (ESI+) m/z: 526.8 ((MH+).

Example 29:2-(6-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridin-3-yl)acetic acid

Step 1: 2-(6-chloropyridine-3-yl)ethyl acetate

2-(6-chloropyridin-3-yl)acetic acid (4 g, 22.4 mmol), ethanol (20 mL)and concentrated sulfuric acid (0.4 mL) were added to a 100 mLsingle-mouth bottle, and heated to 90° C. to react overnight. Afterreaction, the mixture was cooled to room temperature, neutralized withsaturated sodium bicarbonate, and extracted with ethyl acetate. Theorganic layers were combined, the solvent was dried with rotation undervacuum under an increased pressure, and the obtained product separatedby a silica gel column (petroleum ether:ethyl acetate=5:1) to give theproduct (colorless oil, 3.75 g), with a yield of 87.2%. ¹H NMR (400 MHz,CDCl₃) δ 8.28 (d, J=1.5 Hz, 1H), 7.61 (dd, J=8.2, 2.1 Hz, 1H), 7.29 (d,J=8.2 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.25 (t, J=7.1 Hz,3H).

Step 2: 2-(6-cyanopyridine-3-yl)ethyl acetate

2-(6-chloropyridine-3-yl)ethyl acetate (2 g, 10.8 mmol), zinc cyanide(1.88 g, 0.5 mmol), tetrakis(triphenylphosphine)palladium (1.2 g, 0.054mmol), and DMF (10 mL) were added to a 25 mL microwave tube, and reactedat 155° C. for 2 hours and then the reaction mixture was separated by asilica gel column (petroleum ether:ethyl acetate=10:1-5:1) to give theproduct (white solid, 930 mg), with a yield of 48.9%. MS (ESI) m/z:189.0 (M+1).

Step 3: 2-(6-(aminomethyl)pyridine-3-yl)ethyl acetate

2-(6-cyanopyridine-3-yl)ethyl acetate (200 mg), methanol (2 mL),concentrated hydrochloric acid (10 mL), and Pd/C (20 mg) were added to a25 mL single-mouth bottle. The hydrogen gas was introduced to enable themixture to react at room temperature for 10 minutes. After confirmingcompletion of the reaction of materials by TLC, the mixture was filteredby celite, and the filtrate was concentrated under a reduced pressure,which is used for the next reaction directly. MS (ESI) m/z: 195 (M+1).

Step 42-(6-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridin-3-yl)ethylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.3 mmol), DCM (4 mL), and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, and stirred for 10 min under ice bath, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then2-(6-(aminomethyl)pyridine-3-yl)methyl acetate (57 mg, 0.37 mmol) wasadded,

and the reaction was continued under ice bath for 30 min. H₂O (10 mL)was added, and the mixture was washed with saturated ammonium chloride,and extracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography(dichloromethane:methanol=20:1) to give the product (white solid, 20mg), with a yield of 11.9%.

Step 52-(6-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridine-3-yl)aceticacid

2-(6-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridine-3-yl)ethyl acetate (20 mg, 0.037 mmol), lithium hydroxide (4.54mg, 0.11 mmol), ethanol (1 mL), and water (0.3 mL) were added to a 25 mLsingle-mouth bottle, and reacted for 2 hours at room temperature. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethylacetate (10 mL×3). The organic layer was concentrated in vacuo to givethe product (white solid, 15 mg), with a yield of 78.9%. ¹H NMR (400MHz, CD₃OD) δ 8.42 (s, 1H), 7.76 (dd, J=8.0, 1.8 Hz, 1H), 7.60 (s, 2H),7.55-7.48 (m, 1H), 7.45-7.36 (m, 3H), 7.29 (dd, J=7.6, 1.7 Hz, 1H), 4.51(s, 2H), 3.65 (s, 2H). MS (ESI) m/z: 513.8 (M+1).

Example 302-(6-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridin-3-yl)propanoic acid

Step 1: 2-(6-cyanopyridine-3-yl)ethyl isopropanoate

2-(6-cyanopyridine-3-yl)ethyl acetate (300 mg, 1.7 mmol) andtetrahydrofuran (2 mL) were added to a 25 mL dried three-necked bottle,and stirred for 5 minutes under ice bath, and then NaH (75 mg, 1.87mmol) was added in batches to continue to stir for 15 min under icebath. In addition, methyl iodide (241 mg, 1.7 mmol) was taken anddiluted with tetrahydrofuran (1 mL), and added to the reaction mixture,and the reaction was continued under ice bath for 30 min. Aftercompletion of the reaction, the reaction was quenched with water, thereaction mixture was extracted with ethyl acetate, and the organiclayers were combined, the solvent was dried with rotation under areduced pressure, and separated by a silica gel column (petroleumether:ethyl acetate=5:1) to give the product (anhydrous oil, 140 mg),with a yield of 43.5%. MS (ESI) m/z: 205.1 (M+1).

Step 2: 2-(6-(aminomethyl)pyridine-3-yl)ethyl isopropanoate

2-(6-cyanopyridine-3-yl)ethyl isopropylate (140 mg), methanol (2 mL),concentrated hydrochloric acid (5 drops) and Pd/C (15 mg) were added toa 25 mL single-mouth bottle, and hydrogen gas was introduced to enablethem obtained mixture to react at room temperature for 30 minutes. Afterconfirming completion of the reaction of materials by TLC, the mixturewas filtered by celite, and the filtrate was concentrated under areduced pressure, which was used in the next reaction directly. MS (ESI)m/z: 209.1 (M+1).

Step 32-(6-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridine-3-yl)ethylisopropanoate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), DCM (4 mL), and DIEA (120 mg, 0.93 mmol) were added to a 25mL single-mouth bottle, and stirred under ice bath for 10 minutes, andthen triphosgene (35 mg, 0.11 mmol) was added, and the reaction wascontinued under ice bath for 30 min, and then2-(6-(aminomethyl)pyridine-3-yl)ethyl isopropanoate (77 mg, 0.37 mmol)was added,

and the reaction was continued under ice bath for 30 min, then at roomtemperature overnight. H₂O (10 mL) was added, and the mixture was washedwith saturated ammonium chloride, and extracted with dichloromethane (10mL×3), and the organic layers were combined, washed with saturatedsodium chloride (10 mL), dried over anhydrous sodium sulfate, andfiltered, and the filtrate was concentrated in vacuo to obtain a crudeproduct. The crude product was separated by preparative thin layerchromatography (dichloromethane:methanol=20:1) to give the product(white solid, 10 mg), with a yield of 5.81%. MS (ESI) m/z: 555.8 (M+1).

Step 42-(6-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridine-3-yl)isopropylacid

2-(6-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)pyridine-3-yl)ethyl acetate (10 mg, 0.018 mmol), lithium hydroxide (2.17mg, 0.053 mmol), ethanol (1 mL) and water (0.3 mL) were added to a 25 mLsingle-mouth bottle, and reacted for 2 hours at room temperature. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and extracted with ethylacetate (10 mL×3). The organic layer was concentrated in vacuo to givethe product (white solid, 5 mg), with a yield of 52.6%. ¹H NMR (400 MHz,CD₃OD) δ 8.46 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.60 (s, 2H), 7.52 (t,J=8.1 Hz, 1H), 7.48-7.37 (m, 3H), 7.30 (d, J=7.4 Hz, 1H), 4.51 (s, 2H),3.79 (d, J=6.7 Hz, 1H), 1.50 (d, J=7.1 Hz, 3H). MS (ESI) m/z: 527.8(M+1).

Example 313-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)-2-methylphenyl)acetic acid

Step 1: methyl 4-bromo-2-methylphenylacetate

4-bromo-2-methylphenylacetonitrile (1 g, 4.1 mmol) and methanol (10 mL)were added to a 25 mL single-mouth bottle, and then thionyl chloride (5mL) was added under ice bath, and the mixture reacted under ice bath for20 minutes, and then reacted at room temperature overnight. Afterreaction, the mixture was filtered and the solvent was dried withrotation under vacuum to give the product (colorless oil, 630 g), with ayield of 54.3%. ¹H NMR (400 MHz, CDCl₃) δ 7.33 (s, 1H), 7.28 (d, J=8.1Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 3.69 (s, 3H), 3.59 (s, 2H), 2.28 (s,3H). MS (ESI) m/z: 242.9 (MH+).

Step 2: methyl 4-cyano-2-methylphenylacetate

Methyl-4-bromo-2-methylphenylacetate (620 mg, 2.55 mmol), zinc cyanide(448 mg, 3.83 mmol) and N,N-dimethylformamide (10 mL) were added to a 20mL microwave tube. The mixture was nitrogen sparged for 5 min,tetrakis(triphenylphosphine)palladium (301 mg, 0.26 mmol) was added, andstirred and heated to 155° C. for 2 hours under microwave. Aftercompletion of reaction, the mixture was cooled to room temperature, andextracted with ethyl acetate for three times. The organic layers werecombined, washed 5 times with water, and finally washed with saturatedsodium chloride, and the organic layer was concentrated in vacuo to geta crude product. The crude product was separated by a silica gel column(petroleum ether:ethyl acetate=8:1-5:1) to give the product (colorlessoil, 350 mg), with a yield of 71.5%. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d,J=8.2 Hz, 2H), 7.30 (d, J=7.7 Hz, 1H), 3.70 (s, 3H), 3.69 (s, 2H), 2.34(s, 3H). MS (ESI) m/z: 190.1 (MH+).

Step 3: 4-aminomethyl-2-methyl methylphenylacetate

4-cyano-2-methyl methylphenylacetate (200 mg, 1.06 mmol), methanol (2mL), aqueous ammonia (5 drops, 28%) and Raney Ni were added to a 25 mLsingle-mouth bottle, and stirred to react at room temperature for 20 minunder hydrogen environment at an atmospheric pressure, and then thereaction mixture was filtered by celite, and the solvent was dried withrotation under vacuum to give the product (colorless oil, 110 mg), witha yield of 53.9%. MS (ESI) m/z: 194.1 (MH+).

Step 43-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-methylbenzyl)methylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL), and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added to and the reaction wascontinued under ice bath for 10 minutes, and then 4-aminomethyl-2-methylmethylphenylacetate (66 mg, 0.37 mmol) was added, and the reaction wascontinued under ice bath for 30 min. H₂O (10 mL) was added and theobtained mixture was washed with saturated ammonium chloride, andextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=3:1-2:1) to give the product (white solid, 70 mg),with a yield of 41.7%. MS (ESI) m/z: 540.8 (MH+).

Step 5:3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-methylbenzyl)acetic acid

3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-methylbenzyl)methyl acetate (80 mg, 0.15 mmol), lithium hydroxide (18mg, 0.45 mmol), ethanol (2 mL), and water (0.5 mL) were added to a 25 mLsingle-mouth bottle, and reacted at room temperature for 3 hours. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and white solidprecipitated, filtered and the solid was dried in vacuo to give theproduct (white solid, 65 mg), with a yield of 95.5%. ¹H NMR (400 MHz,CD₃OD) δ 7.59 (s, 2H), 7.52 (td, J=7.8, 1.3 Hz, 1H), 7.43 (d, J=7.4 Hz,1H), 7.39 (d, J=8.4 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.20-7.14 (m, 2H),7.12 (d, J=8.1 Hz, 1H), 4.35 (s, 2H), 3.62 (s, 2H), 2.31 (s, 3H). MS(ESI) m/z: 526.8 (MH+).

Example 323-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-fluorophenyl)acetic acid

Step 1: 4-bromo-2-methyl fluorophenylacetate

4-bromo-2-fluorophenylacetonitrile (1 g, 4.67 mmol) and methanol (10 mL)were added to a 25 mL single-mouth bottle, and thionyl chloride (5 mL)was added dropwise under ice bath. After reaction for 20 minutes underice bath, the mixture reacted at room temperature overnight. Afterreaction, the mixture was filtered, and the solvent was dried withrotation under vacuum to give the product (colorless oil, 1 g), with ayield of 86.9%. ¹H NMR (400 MHz, CDCl₃) δ 7.49 (t, J=7.7 Hz, 1H), 7.07(dd, J=9.3, 1.7 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 3.70 (s, 3H), 3.59 (s,2H). MS (ESI) m/z: 245.9 (MH+).

Step 2: 4-cyano-2-methyl fluorophenylacetate

4-bromo-2-ethyl fluorophenylacetate (1.7 g, 6.68 mmol), zinc cyanide(1.21 g, 10.3 mmol), and N,N-dimethylformamide (10 mL) were added to a20 mL microwave tube. The mixture was nitrogen sparged for 5 min,tetrakis(triphenylphosphine)palladium (795 mg, 0.69 mmol) was added, andthe mixture was stirred and heated to 155° C. for 2 hours undermicrowave. After completion of reaction, the mixture was cooled to roomtemperature, and extracted with ethyl acetate for three times. Theorganic layers were combined, washed 5 times with water, finally washedwith saturated sodium chloride, and concentrated under a reducedpressure to get a crude product. The crude product was separated by asilica gel column (petroleum ether:ethyl acetate=8:1-5:1) to give theproduct (colorless oil, 730 mg), with a yield of 55.3%. ¹H NMR (400 MHz,CDCl₃) δ 7.59 (t, 7=7.3 Hz, 1H), 7.19 (d, J=8.7 Hz, 2H), 3.72 (s, 3H),3.69 (s, 2H). MS (ESI) m/z: 194.1 (MH+).

Step 3: 4-aminomethyl-2-methyl fluorophenylacetate

4-cyano-2-methyl fluorophenylacetate (160 mg, 0.81 mmol), methanol (4mL), aqueous ammonia (5 drops, 28%) and Raney Ni were added to a 25 mLsingle-mouth bottle, and hydrogen gas was introduced to react at roomtemperature for 1 hour. The reaction mixture was filtered by celite, andthe solvent was dried with rotation under vacuum to give the product(colorless oil, 140 mg), with a yield of 85.9%. ¹H NMR (400 MHz, CDCl₃)δ 7.29 (d, J=7.7 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.99 (d, J=11.1 Hz,1H), 3.88 (s, 2H), 3.70 (s, 3H), 3.60 (s, 2H), 1.78 (s, 2H). MS (ESI)m/z: 198.1 (MH+).

Step 4:3-(4-((3-(2,6-dichloro-2′-(Trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-fluorobenzyl)methyl acetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL) and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then 4-aminomethyl-2-methylfluorophenylacetate (73 mg, 0.37 mmol) was added, and the reaction wascontinued under ice bath for 30 min. H₂O (10 mL) was added and themixture was washed with saturated ammonium chloride, and extracted withdichloromethane (10 mL×3). The organic layers were combined, washed withsaturated sodium chloride (10 mL), dried over anhydrous sodium sulfate,and filtered, and the filtrate was concentrated in vacuo to obtain acrude product. The crude product was separated by preparative thin layerchromatography (developing agent dichloromethane:methanol=20:1) to givethe product (white solid, 80 mg), with a yield of 40.8%. ¹H NMR (400MHz, CDCl₃) δ 7.85 (s, 1H), 7.44 (m, 1H), 7.38 (s, 2H), 7.34 (d, J=7.9Hz, 2H), 7.22-7.16 (m, 2H), 6.95-6.92 (m, 1H), 6.90 (d, J=6.1 Hz, 1H),6.00 (d, J=2.8 Hz, 1H), 4.32 (d, J=3.0 Hz, 2H), 3.68 (s, 3H), 3.58 (s,2H). MS (ESI) m/z: 544.8 (MH+).

Step 53-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-fluorophenyl)aceticacid3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)

2-fluorophenyl)methyl acetate (80 mg, 0.15 mmol), lithium hydroxide (18mg, 0.45 mmol), ethanol (4 mL) and water (1 mL) were added to a 25 mLsingle-mouth bottle, and reacted at room temperature for 2 hours. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and white solidprecipitated, filtered and the solid was dried in vacuo to give theproduct (white solid, 70 mg), with a yield of 89.7%. ¹H NMR (400 MHz,CD₃OD) δ 7.58 (s, 2H), 7.54-7.49 (m, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.40(s, 1H), 7.37 (d, J=3.7 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 7.31-7.26 (m,1H), 7.08 (t, J=9.7 Hz, 2H), 4.44 (s, 2H), 3.61 (s, 2H). MS (ESI) m/z:530.8 (MH+).

Example 333-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-chlorophenyl)acetic acid

Step 1: methyl 4-bromo-2-chlorophenylacetate

4-bromo-2-chlorophenylacetic acid (1 g, 4.02 mmol), and methanol (10 mL)were added to a 25 mL single-mouth bottle, and then thionyl chloride(0.5 mL) was added to enable the mixture to react at 65° C. for 3 hours.After completion of the reaction, the mixture was concentrated in vacuoto remove the solvent to give the product (colorless oil, 900 mg), witha yield of 84.9%. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (d, J=1.9 Hz, 1H), 7.37(dd, J=8.2, 1.9 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 3.73 (s, 2H), 3.71 (s,3H)

Step 2: methyl 4-cyano-2-chlorophenylacetate

Methyl 4-bromo-2-chlorophenylacetate (1 g, 3.84 mmol), zinc cyanide (539mg, 4.61 mmol) and N,N-dimethylformamide (10 mL) were added to a 20 mLmicrowave tube. The mixture was nitrogen sparged for 5 min,tetrakis(triphenylphosphine)palladium (222 mg, 0.19 mmol) was added, andthe mixture was stirred and heated to 155° C. for 1.5 hours undermicrowave. After completion of reaction, the mixture was cooled to roomtemperature, and extracted with ethyl acetate for three times. Theorganic layers were combined, washed 5 times with water, finally washedwith saturated sodium chloride, and concentrated in vacuo to get a crudeproduct. The crude product was separated by a silica gel column(petroleum ether:ethyl acetate=8:1-5:1) to give the product (yellow oil,350 mg), with a yield of 48.8%. ¹NMR (400 MHz, CDCl₃) δ 7.69 (s, 1H),7.53 (d, J=1.3 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 3.84 (s, 2H), 3.73 (s,4H).

Step 3: methyl 4-aminomethyl-2-chlorophenylacetate

Methyl 4-cyano-2-chlorophenylacetate (350 mg, 1.67 mmol), methanol (2mL), aqueous ammonia (5 drops, 28%), and Raney Ni were added to a 25 mLsingle-mouth bottle, the hydrogen gas was introduced to enable themixture to react for 1 hour while stirring, and then the mixture wasfiltered by celite, and the solvent was dried with rotation under vacuumto obtain a colorless oil, which was directly used in the next reaction.MS (ESI) m/z: 214.0 MIFF).

Step 43-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-chlorophenyl)methylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL), and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then methyl4-aminomethyl-2-chlorophenylacetate (71 mg, 0.37 mmol) was added, andthe reaction was continued under ice bath for 30 min. H₂O (10 mL) wasadded and the obtained mixture was washed with saturated ammoniumchloride, and extracted with dichloromethane (10 mL×3). The organiclayers were combined, washed with saturated sodium chloride (10 mL),dried over anhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=3:1-2:1) to give the product (white solid, 90 mg),with a yield of 51.7%. MS (ESI) m/z: 560.7 (MH+).

Step 53-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-chlorophenyl)acetic acid

3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)2-chlorophenyl)methylacetate (47 mg, 0.084 mmol), lithium hydroxide (11 mg, 0.25 mmol),ethanol (4 mL) and water (1 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and white solid precipitated,filtered and the solid was dried in vacuo to give the product (whitesolid, 35 mg), with a yield of 76.1%. ¹H NMR (400 MHz, CD₃OD) δ12.51-12.29 (m, 1H), 9.18 (s, 1H), 7.64 (s, 2H), 7.57 (t, J=7.0 Hz, 1H),7.47 (t, J=7.0 Hz, 2H), 7.39-7.35 (m, 1H), 7.33 (d, J=7.9 Hz, 2H), 7.20(d, J=9.0 Hz, 1H), 7.04 (s, 1H), 4.28 (d, J=5.8 Hz, 2H), 3.66 (s, 2H).MS (ESI) m/z: 546.7 (MH+).

Example 343-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)-3-methylphenyl)acetic acid

Step 1: methyl 4-bromo-3-methylphenylacetate

4-bromo-3-methylphenylacetonitrile (1 g, 4.76 mmol) and methanol (10 mL)were added to a 25 mL single-mouth bottle, and thionyl chloride (5 mL)was added under ice bath. After reacted under ice bath for 20 minutes,the obtained mixture reacted at room temperature overnight. Aftercompletion of the reaction, the mixture was concentrated in vacuo toremove the solvent to give the product (colorless oil, 1 g), with ayield of 64.1%. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J=8.1 Hz, 1H), 7.15(s, 1H), 6.96 (dd, J=8.2, 1.6 Hz, 1H), 3.69 (s, 3H), 3.55 (s, 2H), 2.38(s, 3H).

Step 2: methyl 4-cyano-3-methylphenylacetate

Ethyl-4-bromo-3-methylphenylacetate (1 g, 4.1 mmol), zinc cyanide (722mg, 6.2 mmol) and N,N-dimethylformamide (10 mL) were added to a 20 mLmicrowave tube. The mixture was nitrogen sparged for 5 min,tetrakis(triphenylphosphine)palladium (237 mg, 0.21 mmol) was added, andthe mixture was stirred and heated to 155° C. for 1.5 hours undermicrowave. After completion of reaction, the mixture was cooled to roomtemperature, and extracted with ethyl acetate for three times. Theorganic layers were combined, washed 5 times with water, and finallywashed with saturated sodium chloride, and the organic layer wasconcentrated in vacuo to remove the solvent to get a crude product. Thecrude product was separated by a silica gel column (petroleumether:ethyl acetate=10:1) to give the product (colorless oil, 360 mg),with a yield of 46.2%. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=7.9 Hz, 1H),7.24 (s, 1H), 7.19 (d, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.64 (s, 2H), 2.53(s, 3H). MS (ESI) m/z: 190.1 (MH+)

Step 3: methyl 4-aminomethyl-3-methylphenylacetate

Methyl 4-cyano-3-methylphenylacetate (350 mg, 1.85 mmol), methanol (5mL), aqueous ammonia (5 drops, 28%) and Raney Ni were added to a 25 mLsingle-mouth bottle, and the hydrogen gas was introduced to react for 1hour at room temperature while stirring. The obtained mixture wasfiltered by celite, and the solvent was dried with rotation under vacuumto give the product (colorless oil, 340 mg), with a yield of 95.2%. MS(ESI) m/z: 194.1 (MI-1+).

Step 43-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)-3-methylphenyl)methylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL) and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then methyl4-aminomethyl-3-methylphenylacetate (72 mg, 0.37 mmol) was added, andthe reaction was continued under ice bath for 30 min. H₂O (10 mL) wasadded and the obtained mixture was washed with saturated ammoniumchloride, and extracted with dichloromethane (10 mL×3). The organiclayers were combined, washed with saturated sodium chloride (10 mL),dried over anhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=5:1-3:1) to give the product (white solid, 90 mg),with a yield of 53.5%. MS (ESI) m/z: 538.8 (M−1)

Step 53-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)-3-methylbenzyl)aceticacid

3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)-3-methylbenzyl)methylacetate (90 mg, 0.17 mmol), lithium hydroxide (21 mg, 0.51 mmol),ethanol (4 mL) and water (1 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and white solid precipitated,filtered and the solid was dried in vacuo to give the product (whitesolid, 37 mg), with a yield of 42.0%. ¹H NMR (400 MHz, DMSO) δ14.32-13.80 (m, 1H), 9.06 (s, 1H), 7.64 (s, 2H), 7.60-7.54 (m, 1H), 7.48(t, J=7.0 Hz, 2H), 7.41-7.35 (m, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.08-7.02(m, 2H), 6.83 (t, J=5.6 Hz, 1H), 4.26 (d, J=5.6 Hz, 2H), 3.49 (s, 2H),2.27 (s, 3H). MS (ESI) m/z: 527.0 (MH+).

Example 353-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)-3-fluorophenyl)acetic acid

Step 1: methyl 4-bromo-3-fluorophenylacetate

4-bromo-3-fluorophenylacetic acid (1 g, 4.3 mmol) and methanol (10 mL)were added to a 25 mL of single-mouth bottle, and thionyl chloride (0.5mL) were added under ice bath, and reacted at room temperature for 3hours. After reaction, the mixture was filtered and the solvent wasdried with rotation under vacuum to give the product (colorless oil, 1.3g), which was directly used in the next step. ¹H NMR (400 MHz, CDCl₃) δ7.49 (t, 7=7.7 Hz, 1H), 7.08 (dd, J=9.3, 1.8 Hz, 1H), 6.95 (dd, J=8.2,1.4 Hz, 1H), 3.71 (s, 3H), 3.59 (s, 2H).

Step 2: methyl 4-cyano-3-fluorophenylacetate

Ethyl-4-bromo-3-fluorophenylacetate (1.3 g, 5.3 mmol), zinc cyanide (924mg, 7.89 mmol) and N,N-dimethylformamide (10 mL) were added to a 20 mLmicrowave tube. The mixture was nitrogen sparged for 5 min,tetrakis(triphenylphosphine)palladium (613 mg, 0.53 mmol) was added, andthe mixture was stirred and heated to 155° C. for 1.5 hours undermicrowave. After completion of reaction, the mixture was cooled to roomtemperature, and extracted with ethyl acetate for three times, and theorganic layers were combined, washed 5 times with water, and finallywashed with saturated sodium chloride, and the organic layer wasconcentrated in vacuo to get a crude product. Then the crude product wasseparated by a silica gel column (petroleum ether:ethyl acetate=8:1-5:1)to give the product (while solid, 620 mg), with a yield of 60.2%. ¹H NMR(400 MHz, CDCl₃) 7.58 (t, J=7.2 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 3.72(s, 3H), 3.69 (s, 2H). MS (ESI) m/z: 194.1 (MH+)

Step 3: methyl-4-aminomethyl-3-fluorophenylacetate

Methyl-4-cyano-3-fluorophenylacetate (350 mg, 1.78 mmol, methanol (4mL), aqueous ammonia (5 drops, 28%) and Raney Ni were added to a 25 mLsingle-mouth bottle, the hydrogen gas was introduced to react for 2hours while stirring, and then the reaction mixture was filtered bycelite, and the solvent was dried with rotation under vacuum to give theproduct (colorless oil, 300 mg), with a yield of 84.0%. MS (ESI) m/z:198.1 MH+).

Step 43-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)3-fluorobenzyl)methylacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL) and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 minutes, and then 4-aminomethyl-methyl3-fluorophenylacetate (73 mg, 0.37 mmol) was added, and the reaction wascontinued under ice bath for 30 min. H₂O (10 mL) was added and theobtained mixture was washed with saturated ammonium chloride, andextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=5:1) to give the product (white solid, 85 mg), witha yield of 50.3%. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.42 (m, 3H), 7.39-7.33(m, 2H), 7.24 (dd, J=7.8, 1.7 Hz, 2H), 7.11 (s, 1H), 7.02-6.93 (m, 2H),4.40 (s, 2H), 3.72 (s, 3H), 3.63 (s, 2H). MS (ESI) m/z: 544.8 (MH+).

Step 53-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)-3-fluorobenzyl)aceticacid

3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)-3-fluorobenzyl)methylacetate (85 mg, 0.16 mmol), lithium hydroxide (20 mg, 0.48 mmol),ethanol (5 mL) and water (1 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 2 hours. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and white solid precipitated,filtered and the solid was dried in vacuo to give the product (whitesolid, 45 mg), with a yield of 54.2%. ¹H NMR (400 MHz, DMSO) δ 12.40 (s,1H), 9.13 (s, 1H), 7.64 (s, 2H), 7.57 (t, J=7.8 Hz, 1H), 7.48 (t, J=7.0Hz, 2H), 7.40-7.35 (m, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.07 (t, J=9.5 Hz,2H), 6.95 (t, J=5.9 Hz, 1H), 4.32 (d, J=5.7 Hz, 2H), 3.57 (s, 2H). MS(ESI) m/z: 530.8 (MH+).

Example 363-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)propanoicacid

Step 1: methyl 4-cyanobenzoate

4-cyanobenzenepropionic acid (1 g, 5.7 mmol) and methanol (10 mL) wereadded to a 25 mL single-mouth bottle, thionyl chloride (0.5 mL) wasadded dropwise at room temperature, and the mixture reacted at roomtemperature for 3 hours while stirring. After the reaction, the mixturewas concentrated in vacuo to remove the solvent under a reducedpressure, and the resulting crude product was dissolved in ethyl acetate(20 mL), and washed with saturated sodium chloride. The organic layerwas dried over anhydrous sodium sulfate, and filtered, and the filtratewas concentrated in vacuo to give the product (colorless oil, 960 mg).¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.1 Hz,2H), 3.66 (s, 3H), 3.00 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H). MS(ESI) m/z: 190.1 (MH+).

Step 2: methyl 4-aminomethyl phenylpropionate

Methyl 4-cyano-phenylpropionate (500 mg, 2.65 mmol), methanol (5 mL),aqueous ammonia (5 drops, 28%) and Raney Ni were added to a 25 mLsingle-mouth bottle, and the hydrogen gas was introduced to enable themixture to react for 3 hours at room temperature while stirring. Afterthe reaction, the mixture was filtered by celite, and the solvent wasdried with rotation under vacuum to give a crude product. The crudeproduct was separated by a silica gel column(dichloromethane:methanol=50:1-25:1) to give the product (while solid,126 mg), with a yield of 24.7%. MS (ESI) m/z: 194.1 (MH+)

Step 3:3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methyl propionate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL) and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then methyl 4-aminomethylphenylpropionate (66 mg, 0.37 mmol) was added, and the reaction wascontinued under ice bath for 30 min, leaving the reaction at roomtemperature for 1 hour. H₂O (10 mL) was added and the obtained mixturewas washed with saturated ammonium chloride, and extracted withdichloromethane (10 mL×3). The organic layers were combined, washed withsaturated sodium chloride (10 mL), dried over anhydrous sodium sulfate,and filtered, and the filtrate was concentrated in vacuo to obtain acrude product. The crude product was separated by a silica gel column(petroleum ether:ethyl acetate=3:1-2:1) to give the product (whitesolid, 110 mg), with a yield of 59.4%. ¹H NMR (400 MHz, CDCl₃) δ 7.87(s, 1H), 7.48-7.41 (m, 1H), 7.40 (s, 2H), 7.34 (d, J=7.5 Hz, 2H), 7.18(dd, 5.2 Hz, 1H), 7.11 (d, J=8.1 Hz, 2H), 7.06 (d, J=8.1 Hz, 2H), 6.00(d, J=1.0 Hz, 1H), 4.26 (s, 2H), 3.62 (s, 3H), 2.86 (t, J=7.7 Hz, 2H),2.56 (t, J=7.7 Hz, 2H). MS (ESI) m/z: 540.8 (MH+).

Step 43-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)propionicacid

3-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)methylpropionate (110 mg, 0.2 mmol), lithium hydroxide (26 mg, 0.6 mmol),ethanol (4 mL) and water (1 mL) were added to a 25 mL single-mouthbottle, and reacted at room temperature for 1 hour. After confirmingcompletion of the reaction of materials by TLC, the mixture was adjustedto pH 3 with 2N hydrochloric acid, and white solid precipitated,filtered and the solid was dried in vacuo to give the product (whitesolid, 90 mg), with a yield of 84.1%. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (s,2H), 7.51 (t, J=11.1, 4.6 Hz, 1H), 7.45-7.37 (m, 2H), 7.29 (d, J=7.7 Hz,1H), 7.26 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.36 (s, 2H), 2.90(t, J=7.6 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H). MS (ESI) m/z: 526.9 (MH+).

Example 372-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-hydroxyaceticacid

Step 1: 4-bromophenyl-2-methyl hydroxyacetate

4-bromophenyl-2-hydroxyacetic acid (2 g, 8.66 mmol) and methanol (10 mL)were added to a 25 mL single-mouth bottle, thionyl chloride (0.5 mL)were added under ice bath, and the obtained mixture reacted at 65° C.for 2 hours. After reaction, the mixture was concentrated in vacuo toremove the solvent, and the resulting crude product was dissolved inethyl acetate, and washed with saturated sodium chloride. The organiclayer was concentrated under a reduced pressure to give the product(white solid, 2.1 g), with a yield of 99%. ¹H NMR (400 MHz, CDCl₃) δ7.49 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 5.14 (s, 1H), 3.76 (s,3H).

Step 2: 4-cyanophenyl-2-methyl hydroxyacetate

4-bromophenyl-2-methyl hydroxyacetate (1 g, 4.1 mmol), zinc cyanide (720mg, 6.1 mmol) and N,N-dimethylformamide (10 mL) were added to a 20 mLmicrowave tube. The mixture was nitrogen sparged for 5 min,tetrakis(triphenylphosphine)palladium (240 mg, 0.2 mmol) was added, andthe mixture was stirred and heated to 155° C. for 1.5 hours undermicrowave. After completion of reaction, the mixture was cooled to roomtemperature, and extracted with ethyl acetate for three times, and theorganic layers were combined, washed 5 times with water, and finallywashed with saturated sodium chloride. The organic layer wasconcentrated in vacuo, and then the crude product was separated by asilica gel column (petroleum ether:ethyl acetate=3:1-2:1) to give theproduct (yellow oil, 450 mg), with a yield of 38.5%. ¹H NMR (400 MHz,CDCl₃) δ 7.67 (d, 7=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 5.25 (s, 1H),3.79 (s, 3H). MS (ESI) m/z: 192.0 (MH+).

Step 3: 4-aminomethylphenyl-2-methyl hydroxyacetate

4-cyanophenyl-2-methyl hydroxyacetate (200 mg, 1.05 mmol), methanol (2mL), aqueous ammonia (10 drops, 28%) and Raney Ni were added to a 25 mLsingle-mouth bottle, the hydrogen gas was introduced to react for 2hours at room temperature while stirring, and then the mixture wasfiltered by celite, and the solvent was dried with rotation under vacuumto give the product (colorless oil, 130 mg), with a yield of 63.7%. MS(ESI) m/z: 196.2 (MH+).

Step 4:2-(4-((3-(2,6-dichloro-2′-(Trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-methylhydroxyacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL) and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then 4-aminomethylphenyl-2-methylhydroxyacetate (72 mg, 0.37 mmol) was added, and the reaction wascontinued under ice bath for 30 min. H₂O (10 mL) was added and theobtained mixture was washed with saturated ammonium chloride, andextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by preparative thin layer chromatography (petroleumether:ethyl acetate=10:1-1:1) to give the product (white solid, 40 mg),with a yield of 23.8%. MS (ESI) m/z: 542.8 (MH+).

Step 5:2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-hydroxyaceticacid

2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-methyl hydroxyacetate (40 mg, 0.07 mmol), lithiumhydroxide (9 mg, 0.21 mmol), ethanol (2 mL) and water (0.5 mL) wereadded to a 25 mL single-mouth bottle, and reacted at room temperaturefor 3 hours. After confirming completion of the reaction of materials byTLC, the mixture was adjusted to pH 3 with 2N hydrochloric acid, andwhite solid precipitated, and filtered to obtain a crude product, andthe crude product was further separated by preparative thin layerchromatography to give the product (white solid, 7 mg), with a yield of17.9%. ¹H NMR (400 MHz, CD₃OD) δ 7.58 (s, 2H), 7.55-7.42 (m, 3H),7.42-7.36 (m, 2H), 7.33 (s, 2H), 7.28 (d, J=7.4 Hz, 1H), 4.40 (s, 2H),2.03 (s, 1H). MS (ESI) m/z: 526.8 (M−1).

Example 382-(4-((3-(2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-fluoroaceticacid

Step 1: methyl-4-bromophenyl-2-fluoroacetate

Methyl 4-bromophenyl-2-fluoroacetate (1 g, 4.1 mmol) (same as the step 1in Example 56) and dichloromethane (10 mL) were added to a 25 mLsingle-mouth bottle, after the obtained mixture was stirred under icebath for 5 minutes, the bottle was added withbis(2-methoxyethyl)aminosulfur trifluoride (1.35 g, 6.1 mmol) dropwise,and the mixture reacted at room temperature overnight. After beingcooled under ice bath, the reaction was quenched by the addition ofsaturated sodium hydrogen carbonate, and the mixture was extracted withdichloromethane (3×20 mL) and washed with saturated sodium chloride. Theorganic layer was concentrated in vacuo to remove the solvent andseparated by a silica gel column (petroleum ether:ethyl acetate=4:1) togive the product (colorless liquid, 720 mg), with a yield of 72%. ¹H NMR(400 MHz, CDCl₃) δ 7.54 (d, J=7.7 Hz, 2H), 7.34 (d, J=7.7 Hz, 2H), 5.75(d, J=47.3 Hz, 1H), 3.78 (s, 3H).

Step 2: methyl 4-cyanophenyl-2-fluoroacetate

Methyl-4-bromo-2-chlorophenylacetate (600 mg, 2.4 mmol), zinc cyanide(426 mg, 3.6 mmol), and N,N-dimethylformamide (10 mL) were added to a 20mL microwave tube. The mixture was nitrogen sparged for 5 min,tetrakis(triphenylphosphine)palladium (138 mg, 0.12 mmol) was added, andthe mixture was stirred and heated to 155° C. for 1.5 hours undermicrowave. After completion of reaction, the mixture was cooled to roomtemperature, extracted with ethyl acetate for three times. The organiclayers were combined, washed for 5 times with water, and finally washedwith saturated sodium chloride, and the organic layer was concentratedunder a reduced pressure to get a crude product. Then the crude productwas separated by a silica gel column (petroleum ether:ethylacetate=10:1) to give the product (yellow oil, 270 mg), with a yield of49.4%.

Step 3: methyl 4-aminomethylphenyl-2-fluoroacetate

Methyl 4-cyanophenyl-2-fluoroacetate (100 mg, 0.52 mmol), methanol (2mL), concentrated hydrochloric acid (5 drops) and Raney Ni were added toa 25 mL single-mouth bottle, and the hydrogen gas was introduced. Thereaction mixture was stirred for 10 minutes at room temperature, andfiltered by celite, and the solvent was dried with rotation under vacuumto obtain a yellow solid, which was used in the next reaction directly.MS (ESI) m/z: 198.1 (MH+).

Step 42-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-methylfluoroacetate

2,6-dichloro-2′-(trifluoromethoxy)-[1,1′-biphenylyl]-4-amine (100 mg,0.31 mmol), dichloromethane (4 mL) and N,N-diisopropylethylamine (120mg, 0.93 mmol) were added to a 25 mL single-mouth bottle, and stirredfor 5 min under ice bath with the protection of nitrogen gas, and thentriphosgene (35 mg, 0.11 mmol) was added, and the reaction was continuedunder ice bath for 10 min, and then 4-aminomethylphenyl-2-methylfluoroacetate (72 mg, 0.37 mmol) was added, and the reaction wascontinued under ice bath for 30 min. H₂O (10 mL) was added and theobtained mixture was washed with saturated ammonium chloride, andextracted with dichloromethane (10 mL×3). The organic layers werecombined, washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, and filtered, and the filtrate wasconcentrated in vacuo to obtain a crude product. The crude product wasseparated by a silica gel column (petroleum ether:ethyl acetate=4:1-2:1)to give the product (white solid, 20 mg), with a yield of 11.8%. ¹H NMR(400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.48-7.40 (m, 3H), 7.37-7.30 (m, 4H),7.28-7.26 (m, 1H), 7.25 (s, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.15 (s, 1H),5.97 (t, J=5.5 Hz, 1H), 5.76 (d, J=47.6 Hz, 1H), 4.36 (d, J=5.4 Hz, 2H),3.74 (s, 4H). MS (ESI) m/z: 544.7 (M−1).

Step 52-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-fluoroaceticacid

2-(4-((3-(2,6-dichloro-2′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)ureido)methyl)phenyl)-2-methylfluoroacetate (20 mg, 0.037 mmol), lithium hydroxide (4.6 mg, 0.11mmol), ethanol (2 mL), and water (0.5 mL) were added to a 25 mLsingle-mouth bottle, and reacted at room temperature for 2 hours. Afterconfirming completion of the reaction of materials by TLC, the mixturewas adjusted to pH 3 with 2N hydrochloric acid, and white solidprecipitated, filtered and the solid was dried in vacuo to give theproduct (white solid, 13 mg), with a yield of 97.4%. ¹H NMR (400 MHz,CD₃OD) δ 7.59 (s, 2H), 7.51 (t, J=7.9 Hz, 1H), 7.49-7.43 (m, 2H),7.43-7.36 (m, 4H), 7.29 (d, J=7.6 Hz, 1H), 5.82 (d, J=48.2 Hz, 1H), 4.43(s, 2H). MS (ESI) m/z: 528.7 (M−1).

Example 39 Determination of Inhibitory Activity of Compounds on RORγReceptors In Vitro

The inhibitory activity of compounds on RORγ receptor was determined byfluorescence resonance energy transfer (FRET) experiments. Theinhibitory activity was expressed by half-inhibitory concentration(IC₅₀).

Experiment Method

1. Preparation of RORγ Buffer Solution

10 mL of DTT and 100 mL buffer solution were gently mixed together andready to use.

2. Preparation of Compound Solution

The concentration of compound solution started from 7.5 mM to 0.25 mM,which was diluted by every 3 folds from 7.5 nM with 10 concentrationstotally.

3. Preparation of Protein Mixture

a. 40 nM B-RORγ LBD solution and 20 nM SA-APC solution were gently mixedtogether. The reaction mixture was incubated for 15 minutes at roomtemperature. Then 400 nM Biotin was added to the described abovemixture. After gently mixed together, the resulting mixture wasincubated for 10 minutes at room temperature.

b. 40 nM Bioin-SRC1 solution and 10 nM SA-eu solution were gently mixedtogether, and the reaction mixture was incubated for 15 minutes at roomtemperature. Then 200 nM Biotin was added to the described abovemixture. After gently mixed together, the resulting mixture wasincubated for 10 minutes at room temperature.

c. The described above two pre-mixes were gently mixed together with aratio of 1:1, and the resulting mixture was incubated for 5 minutes atroom temperature.

d. A mixture of 0.1 μM alternative agonistN-(2-chloro-6-fluorophenyl)-N-((20-methoxy-[1,10-biphenylyl]-4-substituted)methyl)benzenesulfonamide,25 μL B-RORγ LBD/SA-APC and Bioin-SRC1/SA-eu mixture solution with testcompound were added to one of the well of a 384-well plate, then theywere centrifuged for 1 minute at 1000 rpm, and incubated at roomtemperature for 1 hour. The values were read on the Envision microplatedetector and IC₅₀ was calculated. The test results are shown in Table 1.

TABLE 1 Determination Results for RORγ Inhibitory Activity of ExampleCompounds No. IC₅₀ I-1  +++ 1-2  + 1-3  ++ 1-4  +++ 1-5  +++ 1-6  +++1-7  +++ 1-8  ++ 1-9  +++ 1-10 ++ 1-11 +++ 1-12 +++ 1-13 +++ 1-14 ++1-15 +++ 1-16 +++ 1-17 +++ 1-18 ++ 1-19 ++ 1-20 +++ 1-21 +++  1-22a ++ 1-22b ++ 1-23 + 1-24 ++ 1-25 +++ 1-26 ++ 1-27 ++ 1-28 ++ 1-29 +++ 1-30++ 1-31 ++ 1-32 +++ 1-33 +++ 1-34 +++ 1-35 +++ 1-36 ++ 1-37 +++ 1-38 +++The IC₅₀ value is the average of at least two independent tests. +++indicates IC₅₀ < 500 nM; ++ indicates 500 nM ≤ IC₅₀ < 5000 nM; and +indicates 5000 nM ≤ IC₅₀ < 50000 nM. Results: Most of the compounds inthe present disclosure have a strong inhibitory activity on the RORγprotein receptors.

Example 40 Experiment of Inhibition on Mouse Th17 Cell Differentiation

Experimental method: Mouse spleen CD4⁺T cells were isolated anddifferentiated into Th17 cells. CD4⁺T cells were cultured in theenvironment of anti-CD3 (0.25 μg/mL), anti-CD28 (1 μg/mL), anti-IL4 (2μg/mL), anti-IFN-γ (2 μg/mL), TGF-β (5 ng/mL), and IL6 (20 ng/mL), andthen the test compound was added. After 96 hours, the differentiationefficiency of Th17 was analyzed. Before collection of cells, PMA at 50ng/mL and ionomycin at 500 ng/mL were added for stimulation for 4 hours,and the ratio of IL-17 was detected by intracellular staining and flowcytometry. At the same time, we used Live/Dead Cell Dye (Invitrogen)staining method to analyze the cell survival rate, to judge whether thedrug had toxicity to cells, and determine the inhibition rate of thecompound at a concentration of 0.3 μM on IL-17 differentiation by Th 17cells. The results are shown in the Table 2 below.

TABLE 2 Determination result for inhibition experiment for Th17 celldifferentiation No. % inh@0.3 μM I-1  +++ 1-2  + 1-3  ++ 1-4  ++ 1-5 +++ 1-6  ++ 1-7  + 1-8  − 1-9  − 1-10 − 1-11 − 1-12 − 1-13 − 1-14 + 1-15+++ 1-16 + 1-17 +++ 1-18 + 1-19 + 1-20 + 1-21 +  1-22a +  1-22b + 1-23 +1-24 − 1-25 − 1-26 + 1-27 − 1-28 − 1-29 − 1-30 − 1-31 − 1-32 − 1-33 −1-34 − 1-35 − 1-36 − 1-37 − 1-38 − +++ indicates that % inh@0.3 μM iswithin the range of 70 to 100; ++ indicates that % inh@0.3 μM is withinthe range of 40 to 70; + indicates that % inh@0.3 μM is within the rangeof 0 to 40; and − indicates that test is not performed. Results: Somecompounds of the present disclosure have strong inhibition on thedifferentiation of mouse Th17 cells.

1. A method for inhibiting RORγt activity in a subject, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of the compound shown by formula II or a pharmaceuticallyacceptable salt thereof:

wherein: B is phenyl or pyridyl; R₁ is optionally selected from a groupconsisting of hydrogen, methyl, halogen, cyano, hydroxyl, —CF₃, —CHF₂,and —CH₂F; R₁′ is selected from a group consisting of hydrogen, —OCF₃,—OCHF₂, —CF₃ and heteroaryl; R₂ is optionally selected from a groupconsisting of hydrogen, halogen, cyano, hydroxyl, C₁-C₆ alkyl,halogen-substituted C₁-C₆ alkyl, C(O)OR_(a) or cycloalkyl substitutedC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ oxo(azo)heterocycloalkyl, C₁-C₆alkoxyl, halogen-substituted C₁-C₆ alkoxyl, hydroxyl or C₁-C₃ alkoxylsubstituted C₁-C₃ alkyl, phenyl, substituted heteroaryloxyl, C₂-C₆alkenyl, halogen substituted aromatic ketone group, carboxyl or cyanosubstituted heteroaryl, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2),—(CH₂)_(n)C(O)OR_(a), —C(O)NR_(a1)R_(a2); R₃ and R₄ is hydrogen or C₁-C₃alkyl; R₅ and R₆ is hydrogen, C₁-C₃ alkyl or C₁-C₃ alkyl hydroxyl; R₇ isoptionally selected from a group consisting of hydrogen, halogen, cyano,hydroxyl, C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl, C(O)OR_(a) orcycloalkyl substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, phenyl,substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl,heterocyclooxyl, heteroaryl, heteroaryloxyl, C₂-C₆ alkenyl,halogen-substituted aromatic ketone group, carboxyl or cyano substitutedheteroaryl, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2), —(CH₂)_(n)C(O)OR_(a)and —C(O)NR_(a1)R_(a2); Y is a covalent bond, When R₈ is

wherein Z is O, and R₉ is methyl, ethyl, or —NH₂; or Y is—CR_(a1)CR_(a2), R₈ is

R_(a), R_(a1) and R_(a2) are each independently selected from hydrogenor C₁-C₃ alkyl; m, r, t and n are each independently selected from anyinteger value of 0˜2.
 2. The method according to claim 1, wherein m is 1and R₁ is selected from a group consisting of —H, —Cl, —F, and —CH₃. 3.The method according to claim 2, wherein r is 1 and R₂ is selected froma group consisting of —H, —Cl, —F, —CF₃, —OCF₃, —CN, C₁-C₃ alkyl andheteroaryl.
 4. The method according to claim 2, wherein r is 2 and R₂ isselected from a group consisting of —Cl, —F, —CF₃, —OCF₃, —CN, and C₁-C₃alkyl.
 5. The method according to claim 1, wherein R₇ is optionallyselected from a group consisting of hydrogen, halogen, cyano, hydroxyl,and C₁-C₆ alkyl.
 6. The method according to claim 1, wherein thecompound is as shown in Formula III:

wherein: X is CH or N; R₁ is optionally selected from a group consistingof —H, —Cl, —F, and —CH₃; R₁′ is optionally selected from a groupconsisting of —H, —OCF₃, —OCHF₂ and —CF₃; R₂ is optimally selected froma group consisting of —H, —Cl, —F, —CF₃, —OCF₃, —CN and C₁-C₃ alkyl; R₃and R₄ each is hydrogen; R₅ and R₆ each is hydrogen; R₇ is optionallyselected from a group consisting of hydrogen, halogen, cyano, hydroxyl,and C₁-C₆ alkyl; Y is a covalent bond, When R₈ is

wherein Z is O, and R₉ is methyl, ethyl, or —NH₂; or Y is-CR_(a1)R_(a2),R₈ is

R_(a), R_(a1) and R_(a)z are each independently selected from hydrogenor C₁-C₃ alkyl; and r and t are each independently selected from 1 or 2.7. The method according to claim 1, wherein the compound is selectedfrom:


8. The method according to claim 1, wherein the subject has RORγtreceptor related diseases.
 9. The method according to claim 8, whereinthe diseases are multiple sclerosis, rheumatoid arthritis,collagen-induced arthritis, psoriasis, inflammatory bowel disease,encephalomyelitis, clonal disease, asthma, or cancer.
 10. The methodaccording to claim 9, wherein the cancer is prostate cancer.
 11. Amethod for preparing RORγt receptor inhibitors, comprising applying ofthe compound shown by formula II or a pharmaceutically acceptable saltthereof:

wherein: B is phenyl or pyridyl; R₁ is optionally selected from a groupconsisting of hydrogen, methyl, halogen, cyano, hydroxyl, —CF₃, —CHF₂,and —CH₂F; R₁′ is selected from a group consisting of hydrogen, —OCF₃,—OCHF₂, —CF₃ and heteroaryl; R₂ is optionally selected from a groupconsisting of hydrogen, halogen, cyano, hydroxyl, C₁-C₆ alkyl,halogen-substituted C₁-C₆ alkyl, C(O)OR_(a) or cycloalkyl substitutedC₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ oxo(azo)heterocycloalkyl, C₁-C₆alkoxyl, halogen-substituted C₁-C₆ alkoxyl, hydroxyl or C₁-C₃ alkoxylsubstituted C₁-C₃ alkyl, phenyl, substituted heteroaryloxyl, C₂-C₆alkenyl, halogen substituted aromatic ketone group, carboxyl or cyanosubstituted heteroaryl, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2),—(CH₂)_(n)C(O)OR_(a), —C(O)NR_(a1)R_(a2); R₃ and R₄ is hydrogen or C₁-C₃alkyl; R₅ and R₆ is hydrogen, C₁-C₃ alkyl or C₁-C₃ alkyl hydroxyl; R₇ isoptionally selected from a group consisting of hydrogen, halogen, cyano,hydroxyl, C₁-C₆ alkyl, halogen-substituted C₁-C₆ alkyl, C(O)OR_(a) orcycloalkyl substituted C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆oxo(azo)heterocycloalkyl, C₁-C₆ alkoxyl, halogen-substituted C₁-C₆alkoxyl, hydroxyl or C₁-C₃ alkoxyl substituted C₁-C₃ alkyl, phenyl,substituted phenyl, phenoxyl, substituted phenoxyl, heterocyclyl,heterocyclooxyl, heteroaryl, heteroaryloxyl, C₂-C₆ alkenyl,halogen-substituted aromatic ketone group, carboxyl or cyano substitutedheteroaryl, —C(O)R_(a), —(CH₂)_(n)NR_(a1)R_(a2), —(CH₂)_(n)C(O)OR_(a)and —C(O)NR_(a1)R_(a2); Y is a covalent bond, When R₈ is

wherein Z is O, and R₉ is methyl, ethyl, or —NH₂; or Y is—CR_(a1)CR_(a2), R₈ is

R_(a), R_(a1) and R_(a2) are each independently selected from hydrogenor C₁-C₃ alkyl; m, r, t and n are each independently selected from anyinteger value of 0˜2.